Cleavage of proteins in the extracellular milieu, including hormones, growth factors and their receptors, ion channels, and various cell adhesion and extracellular matrix molecules, plays a key role in the regulation of cell behavior. Among more than 500 proteolytic enzymes encoded by mammalian genomes, membrane-anchored serine proteases (MASPs), which are expressed on the surface of epithelial cells of all major organs, are excellently suited to mediate signal transduction across the epithelia and are increasingly being recognized as important regulators of epithelial development, function, and disease [ 1–3]. In this minireview, we summarize current knowledge of the in vivo roles of MASPs in acquisition and maintenance of some of the defining functions of epithelial tissues, such as barrier formation, ion transport, and sensory perception.

Membrane-anchored serine proteases (MASPs)

The human MASP family currently comprises 20 proteases, with orthologs identified in all vertebrate species analyzed to date (Figure 1). Based on their membrane topology, the majority of the MASPs are classified as type II transmembrane serine proteases (TTSPs) that are anchored to the membrane via a single-pass transmembrane domain located near the amino terminus. This is followed by a variable stem region and an extracellular carboxy-terminal trypsin-like serine protease domain. Based on the sequence similarities between the catalytic domains, TTSPs have been further divided into four distinct sub-families [1]. Type I MASPs include three proteases that are composed of an extracellular serine protease domain attached to the membrane via a C terminal transmembrane domain (tryptase γ1) or a glycosylphosphatidylinositol (GPI) anchor (prostasin and testisin).

Classification and domain structure of human membrane-anchored serine proteases.

Figure 1.
Classification and domain structure of human membrane-anchored serine proteases.
Figure 1.
Classification and domain structure of human membrane-anchored serine proteases.

All MASPs belong to the S1 family of serine endoproteases that includes trypsin as the prototypic member and show a strong preference for cleavage of substrates after arginine or lysine residues [4]. MASPs are synthesized as single-chain zymogens that undergo proteolytic cleavage at a conserved site within the catalytic domain, thus producing a fully active double-chain form [1]. While this has long been considered an essential step towards the activation of an essentially inactive zymogen, recent findings suggest that at least some MASPs are capable of performing their biological function independent of activation cleavage [5,6].

MASPs in development and maintenance of epithelial barriers

Matriptase/prostasin system as general regulator of epithelial barrier function

Epithelia provide barriers that protect tissues from external physical, chemical, and microbial insults and maintain fluid homeostasis. The paracellular barrier, which limits permeability between epithelial cells, is critical to maintain transepithelial ion and nutrient gradients, and is a principal defense mechanism preventing entry of pathogens and toxic substances [7]. The barrier is primarily regulated at the level of tight junctions (TJs) that are expressed at the apical margin of epithelial junctional complexes and restrict paracellular diffusion [7,8]. The notion that proteolysis may be involved in the regulation of paracellular barrier function was suggested based on the observation that a mild treatment of cultured epithelial cells with endoproteases leads to rapid assembly of TJ strands and strengthening of the barrier [9,10].

The TTSP matriptase and its proposed activator, prostasin, are expressed in the epithelial compartments of most human and mouse tissues [11]. The critical role of the prostasin/matriptase system in epithelial barrier formation was first inferred from the study of genetically modified mice (Table 1). Mice lacking matriptase develop to term but exhibit abnormal terminal differentiation of epidermal keratinocytes, and loss of epidermal barrier function that results in fatal postnatal dehydration [12,13]. These phenotypes closely match those observed in mice lacking epidermal prostasin, consistent with a proposed functional interaction between the two proteases during skin development [14,15].

Table 1.
Defects in epithelial barrier function resulting from loss of matriptase activity
OrganismLoss of matriptase functionPhenotypeBarrier defect
Human 
ARIH (OMIM#602400) [23Expected partial to complete, all tissues Skin — ichthyosis, hypotrichosis, dysplastic hair
Teeth — enamel notching/pitting, conical primary teeth
Eye — Corneal opacity, photophobia 
 
Mouse 
St14−/− [12,13Null, all tissues Perinatal lethality within 48 h after birth
Skin — Defects in stratum corneum development, ichthyosis, hair follicle hypoplasia, lack of whiskers
Thymus — increased thymocyte apoptosis 
Increased transepidermal fluid loss and diffusion of topically or intradermally injected tracers, loss of TJ localization of ZO1 
St14−/− in PAR2-deficient background [17Null, all tissues Embryonic lethality
Placenta — underdevelopment of labyrinth layer 
Increased transplacental diffusion, decreased expression of claudin 1 
Vil-Cre;St14fl/fl [13,27Null, epithelium of GI tract Growth retardation, diarrhea, shortened lifespan
Colon — Edema, loss of crypt architecture, severe inflammation 
Increased transepithelial diffusion of intestinal luminal biotin into tissue stroma 
MMTV-Cre;St14fl/fl [13,16Null, epithelium of salivary glands Loss of saliva production Increased transepithelial electrical conductance in salivary gland, loss of membrane localization of claudin 3 
βAct-CreERTM;St14fl/fl [13Inducible loss of expression, all tissues Rapid loss of weight and viability
Skin — loss of hair, ichthyosis
Colon — edema, loss of crypt structure, inflammation 
Skin — decreased expression of TJ proteins claudin1, ZO1, and occludin
Intestine — increased transepithelial diffusion of intestinal luminal dextran into bloodstream 
St14hypo/hypo [25Reduced expression, all tissues Skin — ichthyosis, epidermal acanthosis, impaired desquamation, delayed hair growth, sparse fur Skin — increased transepidermal fluid loss
Intestine — decreased transepithelial electrical resistance, increased diffusion intestinal luminal dextran into bloodstream, increased expression of claudin 2 
Horse 
ST14:c.388G > T [22Null, all tissues Skin — dry and scaly, complete alopecia
Thymus — lack of cortico-medullary organization, absence of Hassal corpuscles
Spleen, lymph nodes — abnormal or absent T cell zones 
 
Fruit fly 
NpP6/NpC2 [24Null, all tissues Lack of airway fluid clearance, embryonic lethality Trachea — increased diffusion of dextran the lumen 
OrganismLoss of matriptase functionPhenotypeBarrier defect
Human 
ARIH (OMIM#602400) [23Expected partial to complete, all tissues Skin — ichthyosis, hypotrichosis, dysplastic hair
Teeth — enamel notching/pitting, conical primary teeth
Eye — Corneal opacity, photophobia 
 
Mouse 
St14−/− [12,13Null, all tissues Perinatal lethality within 48 h after birth
Skin — Defects in stratum corneum development, ichthyosis, hair follicle hypoplasia, lack of whiskers
Thymus — increased thymocyte apoptosis 
Increased transepidermal fluid loss and diffusion of topically or intradermally injected tracers, loss of TJ localization of ZO1 
St14−/− in PAR2-deficient background [17Null, all tissues Embryonic lethality
Placenta — underdevelopment of labyrinth layer 
Increased transplacental diffusion, decreased expression of claudin 1 
Vil-Cre;St14fl/fl [13,27Null, epithelium of GI tract Growth retardation, diarrhea, shortened lifespan
Colon — Edema, loss of crypt architecture, severe inflammation 
Increased transepithelial diffusion of intestinal luminal biotin into tissue stroma 
MMTV-Cre;St14fl/fl [13,16Null, epithelium of salivary glands Loss of saliva production Increased transepithelial electrical conductance in salivary gland, loss of membrane localization of claudin 3 
βAct-CreERTM;St14fl/fl [13Inducible loss of expression, all tissues Rapid loss of weight and viability
Skin — loss of hair, ichthyosis
Colon — edema, loss of crypt structure, inflammation 
Skin — decreased expression of TJ proteins claudin1, ZO1, and occludin
Intestine — increased transepithelial diffusion of intestinal luminal dextran into bloodstream 
St14hypo/hypo [25Reduced expression, all tissues Skin — ichthyosis, epidermal acanthosis, impaired desquamation, delayed hair growth, sparse fur Skin — increased transepidermal fluid loss
Intestine — decreased transepithelial electrical resistance, increased diffusion intestinal luminal dextran into bloodstream, increased expression of claudin 2 
Horse 
ST14:c.388G > T [22Null, all tissues Skin — dry and scaly, complete alopecia
Thymus — lack of cortico-medullary organization, absence of Hassal corpuscles
Spleen, lymph nodes — abnormal or absent T cell zones 
 
Fruit fly 
NpP6/NpC2 [24Null, all tissues Lack of airway fluid clearance, embryonic lethality Trachea — increased diffusion of dextran the lumen 

Roles of matriptase in other epithelia have been documented using tissue-specific mouse knockouts. Inactivation of the protease results in a loss of saliva production by salivary glands and a disruption of normal tissue architecture within the large intestine that results in diarrhea, growth retardation and shortened life span [13,16]. In both organs, elimination of matriptase expression leads to a diminished epithelial barrier function (Table 1) [13,16]. Inactivation of matriptase also significantly increased leakiness of placental epithelia and led to embryonic lethality in mice lacking the G protein-coupled receptor PAR2 [17]. Mice and rats carrying hypomorphic mutations in Prss8, encoding prostasin, also exhibit defects in intestinal and placental function, although it is not clear whether any of these defects are related to altered matriptase activity [18–21].

In humans and in horses, loss-of-function mutations in ST14, encoding matriptase, have been linked to autosomal recessive ichthyosis with hypotrichosis (OMIM#602400) and Naked Foal Syndrome, respectively [22,23]. Both diseases present with skin defects that include mild to moderate ichthyosis, indicative of compromised epidermal barrier function (Table 1). Finally, the matriptase and prostasin homologs, Notopleural and Tracheal-prostasin, are essential for the establishment of airway barrier function and embryonic survival in Drosophila (see below) [24]. Consistent with the in vivo studies, inhibition or elimination of matriptase activity results in decreased ability of cultured intestinal and kidney epithelial cells to establish and maintain fully functional barriers [25,26].

Despite the overwhelming evidence for the importance of matriptase for epithelial barrier development, the molecular mechanisms underlying this function remain unknown. Loss of matriptase expression leads to a decreased expression and/or recruitment of several barrier-promoting tight junction-associated proteins, including claudin-1, occludin, and ZO-1, while also increasing expression of permeability-associated protein claudin-2 both in mouse epithelia and in cultured human intestinal epithelial cells [13,17,25,27]. Therefore, it is plausible to hypothesize that matriptase promotes epithelial barrier function by regulating assembly and/or stability of barrier-forming junctions. However, as of now, no evidence has been presented to indicate that barrier stability is regulated by a proteolytic cleavage of any of the core components of epithelial junctional complexes.

Although the ability of matriptase to cleave and to regulate the activity of many biologically active molecules in vitro is well documented, attempts to validate the involvement of any of these substrates in matriptase-mediated regulation of epithelial development and barrier formation have been unsuccessful. Genetic inactivation of either hepatocyte growth factor (HGF) receptor, cMet, or a G protein-coupled receptor PAR-2, prevent matriptase-driven tumorigenesis in mouse skin, indicating the ability of matriptase to stimulate HGF- and PAR-2-mediated cell signaling in vivo [28,29]. PAR-2 inactivation also rescued ichthyosis in mice overexpressing prostasin in the skin and matriptase-induced defects in epidermal development in zebrafish embryos [30,31]. Likewise, the epithelial sodium channel (ENaC) is activated by prostasin or matriptase in Xenopus oocytes and in mice (see also ‘MASPs in the regulation of transepithelial ion transport’ below) [32]. However, loss of PAR-2, HGF, or ENaC in mice does not appear to reproduce any of the phenotypes observed in matriptase-deficient mice, indicating that activation of any of these three molecules does not critically contribute to the matriptase-mediated formation of epithelial barrier function [33–36].

Recently, epithelial cell adhesion molecule (EpCAM) was proposed to be a pathogenic substrate for matriptase during intestinal development. Inactivating mutations in EPCAM are found in patients with congenital tufting enteropathy (CTE, OMIM #613217), an early-onset severe intestinal insufficiency characterized by epithelial dysplasia and villous atrophy leading to chronic watery diarrhea and failure to thrive [37]. EpCAM is efficiently cleaved by matriptase in cell culture systems, and loss-of-function mutations in SPINT2, encoding the endogenous inhibitor of the matriptase/prostasin pathway, HAI-2, are responsible for the syndromic form of CTE (OMIM #270420) [38,39]. Furthermore, two recently generated HAI-2-deficient mouse models exhibit severe intestinal insufficiency that resembles that of CTE patients, including compromised intestinal epithelial barrier and loss of EpCAM protein expression [40,41]. In one of the models, early onset intestinal defects caused by HAI-2 deficiency were suppressed by genetic inactivation of matriptase, indicating that the intestinal failure in this model of CTE is, in part, matriptase-driven [42]. It was, therefore, suggested that an increased matriptase-mediated cleavage and subsequent degradation of EpCAM in mice and humans lacking functional HAI-2 may be involved in the etiology of the disease. However, whether increased cleavage of EpCAM indeed drives intestinal failure CTE in HAI-2-deficient mice and humans remains to be determined. Furthermore, it is not clear if EpCAM processing has a physiological role in matriptase-mediated barrier acquisition in HAI-2-competent tissues during normal development.

Epidermal barrier formation — Tmprss13 and Tmprss11f

In addition to matriptase/prostasin pathway, the TTSPs TMPRSS13 and TMPRSS11F contribute to epidermal barrier formation in mouse skin. Both proteases are expressed in a wide array of mouse and human tissues, with high levels detected in keratinized epithelia of skin, oral cavity and upper digestive system [43–46]. Both Tmprss13- and Tmprss11f-deficient newborn mice present with significantly increased transepidermal fluid loss, indicative of compromised epidermal barrier function [44,47,48]. The rate of fluid loss is relatively small compared with that observed in mice lacking either matriptase or prostasin, and it does not affect postnatal development or long-term survival of Tmprss13- or Tmprss11f-deficient mice, suggesting that at least in the absence of additional challenge, the individual contribution of the two proteases to the establishment of the epidermal barrier is relatively minor. Loss of TMPRSS11F did not alter the histological appearance of the epidermis, including stratum corneum, or the expression of any of the major components of the cornified envelope, whereas newborn Tmprss13-deficient mice exhibit reduced stratum corneum thickness, but no obvious defects in TJ function or profilaggrin processing analogous to the ones observed in matriptase- and prostasin-deficient epidermis [44,48]. It is, therefore, unclear whether the two proteases contribute to the formation of epidermal barrier function either in parallel or as one of several functionally relevant targets acting downstream of the matriptase/prostasin system.

MASPs in the regulation of transepithelial ion transport

Activation of the epithelial sodium channel — prostasin, matriptase, TMPRSS4

Directional transport of ions and water across epithelial barriers is essential for maintaining tissue homeostasis and is a critical function of all polarized epithelia. The ENaC is a key component of sodium (Na+) transport across high resistance epithelia and is crucial for salt tasting in tongue epithelium and sodium reabsorption in kidney, lungs, and intestines, thus regulating blood pressure, blood potassium levels, and airway and alveolar surface liquid volumes [32]. Many extracellular proteases of serine, cysteine, and metalloproteinase families, including membrane-tethered serine proteases prostasin, matriptase, TMPRSS4, and TMPRSS3, have been shown to activate ENaC in a variety of in vitro and in vivo systems by proteolytic cleavage and removal of an inhibitory tract from its γ subunit [32,49].

The importance of prostasin-dependent activation of ENaC has been demonstrated using a series of tissue-specific prostasin-deficient mice. In lungs, the level of airway surface liquid (ASL) that covers the apical surface of the airway epithelium is critical for alveolar function and is maintained by moving ASL across the epithelium in a process that is facilitated by ENaC-mediated sodium absorption [50]. Mice lacking prostasin in alveolar epithelial cells show 40% decrease in ENaC-mediated sodium currents and a reduced sodium-driven alveolar clearance, leading to a fluid accumulation in an experimental model of hydrostatic pulmonary edema [51]. Aberrant activity of channel-activating proteases may also be involved in the etiology of pulmonary fibrosis. TMPRSS4 and matriptase are up-regulated during bleomycin-induced lung fibrosis in mice, and genetic ablation of either of the two proteases or treatment with the serine protease inhibitor, camostat mesilate, attenuates the development of the disease [52,53]. Similarly, intratracheal administration of camostat mesilate inhibits ENaC activity in guinea pigs and enhances mucociliary clearance in sheep [54]. Furthermore, in cultured primary airway epithelial cells from cystic fibrosis patients, who often suffer from mucus plugging and chronic bacterial infection due to reduced ASL, inhibition of ENaC-activating proteases increased ASL height and improved mucociliary function [55].

Essential functions of ENaC-mediated sodium transport in kidneys have been documented in patients with hypertension associated with inherited forms of hypokalemia (Liddle syndrome, OMIM#177200), or hypotension associated with hyperkalemia (pseudohypoaldosteronism type 1, OMIM#264350), that carry, respectively, gain-of-function and loss-of-function mutations in genes encoding ENaC subunits [56]. Although kidney tubule-specific prostasin knockout has not yet been described, the administration of the non-selective serine protease inhibitors, aprotinin and camostat mesilate, both led to an increased excretion of sodium in mice and reduced blood pressure and renal injury in a salt-sensitive hypertension rat model, consistent with serine protease-dependent activation of ENaC [57,58]. Reduced ENaC-mediated sodium transport has also been reported in the colon of mice that carry a partial loss-of-function mutation or intestine-specific inactivation of the prostasin gene [18,20].

Whether the regulation of sodium transport plays a role in the barrier-promoting function of the matriptase/prostasin system is not clear. However, barrier acquisition did not appear to be significantly affected in alveolar epithelial cells or colons of prostasin-deficient mice, indicating that two of the proposed physiological functions of prostasin, establishment of epithelial barrier and regulation of transepithelial ion transport, may not be directly linked [20,51].

Regulation of blood pressure and kidney function — corin, hepsin

The TTSP corin is essential for proteolytic activation of pro-atrial natriuretic peptide (pro-ANP), a pro-form of a cardiac hormone ANP that regulates water–salt balance and blood pressure by promoting excretion of both sodium and water by the kidneys [59]. Loss-of-function mutations in CORIN are associated with hypertension, edema and heart failure in humans, and with impaired renal sodium excretion, salt-sensitive hypertension, water retention and cardiac hypertrophy in mice [59–61]. While natriuretic peptides and corin are mainly produced by the heart, both pro-ANP and corin are expressed in several non-cardiac tissues involved in blood pressure regulation, including placenta and kidney [62,63]. In the kidney, corin is expressed at the apical membrane of epithelial cells along the entire length of the nephron, where it is believed to process filtered and/or locally produced pro-ANP [63]. Mature ANP decreases sodium reabsorption and urine-concentrating capacity by inhibiting several sodium transport systems, most notably the Na–K-ATPase, Na/H exchanger, and type IIa Na–Pi cotransporter in the proximal tubule, and by inhibiting Cltransport via decreasing apical membrane expression of Na–K–2Cl cotransporter (NKCC2) in the distal tubule (Figure 2) [64]. Natriuretic and diuretic effects of ANP also involve suppression of both ENaC-mediated sodium reabsorption and vasopressin-stimulated water reabsorption in collecting ducts of the kidney [65]. Consistent with this, impaired sodium excretion and increased water retention in corin-deficient mice were suppressed by treatment with an ENaC inhibitor, amiloride [60].

Proposed roles of MASPs in the regulation of ion transport in the kidneys.

Figure 2.
Proposed roles of MASPs in the regulation of ion transport in the kidneys.

Corin-generated ANP binds to its receptor NPR-A and enhances its guanylyl cyclase activity. CyclicGMP prevents sodium reabsorption by inhibiting the activity of several ion transport proteins in different segments of the nephron. Hepsin mediates shedding of the GPI-anchored protein uromodulin, leading to a decreased activity of Na+, K+, Cl cotransporter NKCC2 in the thick ascending limb. Finally, several MASPs, including prostasin, matriptase, and TMPRSS4, have been proposed to activate the epithelial sodium channel ENaC, suggesting their possible involvement in sodium reabsorption in the distal tubules and collecting ducts. Abbreviations: ANP, atrial natriuretic peptide; cGMP, cyclic guanosine monophosphate; ENaC, epithelial sodium channel; GPI, glycosylphosphatidylinositol, GTP, guanosine triphosphate; Na/K ATPase, sodium–potassium adenosine triphosphatase; NaPi-IIa, sodium–phosphate cotransporter IIa; NHE, sodium–proton exchanger; NKCC2, sodium–potassium–chloride cotransporter; NPR, natriuretic peptide receptor.

Figure 2.
Proposed roles of MASPs in the regulation of ion transport in the kidneys.

Corin-generated ANP binds to its receptor NPR-A and enhances its guanylyl cyclase activity. CyclicGMP prevents sodium reabsorption by inhibiting the activity of several ion transport proteins in different segments of the nephron. Hepsin mediates shedding of the GPI-anchored protein uromodulin, leading to a decreased activity of Na+, K+, Cl cotransporter NKCC2 in the thick ascending limb. Finally, several MASPs, including prostasin, matriptase, and TMPRSS4, have been proposed to activate the epithelial sodium channel ENaC, suggesting their possible involvement in sodium reabsorption in the distal tubules and collecting ducts. Abbreviations: ANP, atrial natriuretic peptide; cGMP, cyclic guanosine monophosphate; ENaC, epithelial sodium channel; GPI, glycosylphosphatidylinositol, GTP, guanosine triphosphate; Na/K ATPase, sodium–potassium adenosine triphosphatase; NaPi-IIa, sodium–phosphate cotransporter IIa; NHE, sodium–proton exchanger; NKCC2, sodium–potassium–chloride cotransporter; NPR, natriuretic peptide receptor.

Corin mutations that impair the natriuretic peptide-processing activity have also been identified in patients with pregnancy-associated hypertension (pre-eclampsia) [62]. Corin expression was detected in decidual cells in the pregnant uterus in mice and in humans, and within late secretory endometrium and in villous cytotrophoblasts from first-trimester placenta, and uterine corin expression was significantly lower in individuals with pre-eclampsia, compared with normal pregnancies [62,66,67]. Histological analysis of placentas from corin-deficient mice and patients with pre-eclampsia revealed delayed trophoblast invasion and impaired spiral artery remodeling in the uterus [62,68,69]. Pregnant mice lacking corin or ANP develop high blood pressure and proteinuria that is not prevented by heart-specific re-expression of corin that restored pro-ANP processing in the heart and normalized blood pressure in non-pregnant mice, suggesting that decreased local uterine, rather than cardiac, corin activity is critical for the development of pre-eclampsia [62,70].

Hepsin regulates sodium transport and homeostasis in the kidney via processing of the GPI-anchored, zona pellucida (ZP)-type protein, uromodulin, that is expressed on the apical surface of kidney epithelial cells within the thick ascending limb of loop of Henle [71,72]. Mutations in the uromodulin gene cause medullary cystic kidney disease 2 (OMIM #603860) and familial juvenile hyperuricemic nephropathy (OMIM#162000) and have been associated with increased risk of chronic kidney disease, calcium stones, and hypertension [73–75]. Uromodulin appears to modulate ion reabsorption by regulating the surface abundance and activity of the sodium, potassium, chloride cotransporter, NKCC2, and the potassium channel, ROMK2 [76,77]. Hepsin mediates proteolytic cleavage and subsequent shedding of uromodulin from the cell surface, and loss of hepsin function leads to hyperactivation of the NKCC2 transporter and increased sodium and water reabsorption (Figure 2) [71,72]. Prolonged exposure of hepsin-deficient mice to the high-salt diet resulted in severe deterioration of renal function with salt wasting and subsequent rise in plasma osmolarity, hypocalcemia, and hypomagnesemia, underscoring the importance of hepsin-mediated processing of uromodulin in the regulation of salt homeostasis and kidney function [72].

Development of hearing — TMPRSS3, hepsin

The ability to perceive sound depends on the proper functioning of the cochlea, a spiral organ within the inner ear with a specialized epithelium that contains electro conducting hair cells for detecting vibrations from the outer and middle ear and converting them into nerve impulses [78]. Loss-of-function mutations in TMPRSS3 causes non-syndromic autosomal recessive deafness (DFNB8/10, OMIM#601072), characterized by early onset, progressive, bilateral hearing loss [79]. Similarly, mice lacking a functional Tmprss3 protein exhibit severe loss of hearing associated with rapid degeneration of cochlear and vestibular hair cells [80]. Prior to degeneration, loss of Tmprss3 reduced the number of Ca2+-activated K+ (BK) channels and decreased expression of several intracellular calcium-binding proteins in cultured primary hair cells, and decreased expression of the α subunit of the BK channel and a loss of BK-dependent fast K+ conductance within the cochlea of Tmprss3-deficient mice [81,82]. Furthermore, activation of the wildtype, but not the deafness-causing variants of Tmprss3 increases amiloride-sensitive sodium transport in a Xenopus oocyte expression system, indicating that the protease could potentially be involved in activation of inner ear-expressed ENaC [49]. However, pseudohypoaldosteronism type 1 patients carrying inactivating mutations in the alpha subunit of ENaC have normal hearing, thus challenging the notion that ENaC activation is crucial for auditory system development [83]. Interestingly, deficiency in hepsin also leads to loss of hearing function in mice and is associated with reduced levels of BK channels in the sensory hair cells, indicating that the two proteases may regulate the development of hearing function via overlapping mechanisms, possibly even as parts of the same proteolytic cascade regulating ion transport in the inner ear [84].

MASPs in extracellular matrix remodeling — lessons from Drosophila

Drosophila Notopleural and Trp, which encode proteases homologous to, respectively, human matriptase and prostasin, have recently been shown to be essential for degradation of intraluminal chitin in the trachea of Drosophila, leading to a defect in barrier function, impaired tracheal liquid clearance and death before hatching [24]. Notopleural mutant and Trp knockdown embryos show defects in cleavage of apical ECM ZP protein Dumpy, which plays an important role in attachment of the epithelium to the exoskeleton at later stages of Drosophila development [85]. Interestingly, depletion of Stubble (Sb-sbd), encoding a TTSP homologous to Notopleural, impairs degradation of Dumpy in epithelial cells within imaginal discs during morphogenesis, and therefore inhibits elongation and expansion of wings and legs [86]. Although Dumpy does not have a homolog in mammalian systems, the recent discovery of hepsin-mediated cleavage of another ZP protein, uromodulin, in mammalian kidney (see above) indicates that cleavage of ZP domain-containing proteins may present an evolutionary-conserved means of regulating epithelial function by cell surface-linked proteolysis.

MASPs in viral processing

Respiratory epithelium is a point of entry into the organism for many pathogens, including viruses. Many enveloped viruses, including influenza A and B, depend on a cleavage of hemaglutinin (HA)-type surface glycoproteins for viral entry into the target cell [87,88]. Several trypsin-like serine proteases, including airway epithelium-expressed TTSPs TMPRSS2, TMPRSS4, TMPRSS13, TMPRSS11A, TMPRSS11D/HAT, TMPRSS11E/DESC1, and matriptase, activate influenza HA and promote infectivity in cell culture systems [88,89]. Recently, TMPRSS2 was identified as a susceptibility gene for Severe 2009 Pandemic A(H1N1) and A(H7N9) Influenza, and inactivation of either TMPRSS2 or TMPRSS4 confers partial to complete resistance to the spread and pathogenesis of influenza virus in mice [90–95]. Surface proteins of several other types of viruses, including Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS-CoV), parainfluenza viruses, human metapneumovirus (HMPV), and Sendai virus (SeV), undergo TTSP-mediated activation cleavage in culture, indicating a potential widespread role of MASPs in viral respiratory illnesses that makes these enzymes potential targets for new antiviral therapies [96–102].

Perspectives

  • Importance of the field: MASPs are critical regulators of epithelial physiology. Changes in MASP expression and/or activity underlie the etiology of numerous diseases and developmental defects in both humans and in animal models.

  • Current thinking: Localization to the cell surface makes MASPs ideal instruments of regulation of cell behavior by extracellular stimuli. Significant progress has been made in recent years to uncover some of the molecular mechanisms of MASP-mediated regulation of epithelial function, including activation of pro-ANP in kidney and placenta, processing of ZP proteins in kidney and tracheal system in Drosophila, or activation cleavage of viral surface proteins.

  • Future directions: Imaging and analyzing the activity of individual proteases in living tissues using highly selective antibodies and activity probes will be crucial to provide further insight into physiological and pathological roles of MASPs, as well as into the mechanisms that govern their expression, cell localization, zymogen activation, and modulation of their proteolytic activity by auxiliary proteins. Development of selective inhibitors of matriptase and other MASPs shown to contribute to disease development may open alternative new strategies to treat conditions such as CTE or viral respiratory infections.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Acknowledgements

This work was supported by the Intramural Research Program at the National Institute of Dental and Craniofacial Research.

Abbreviations

     
  • ASL

    airway surface liquid

  •  
  • CTE

    congenital tufting enteropathy

  •  
  • ENaC

    epithelial sodium channel

  •  
  • EpCAM

    epithelial cell adhesion molecule

  •  
  • GPI

    glycosylphosphatidylinositol

  •  
  • HGF

    hepatocyte growth factor

  •  
  • MASPs

    membrane-anchored serine proteases

  •  
  • NKCC2

    Na-K-2Cl cotransporter

  •  
  • pro-ANP

    pro-atrial natriuretic peptide

  •  
  • SeV

    sendai virus

  •  
  • TTSPs

    type II transmembrane serine proteases

  •  
  • ZP

    zona pellucida

References

References
1
Szabo
,
R.
and
Bugge
,
T.H.
(
2011
)
Membrane-anchored serine proteases in vertebrate cell and developmental biology
.
Annu. Rev. Cell Dev. Biol.
27
,
213
235
2
Antalis
,
T.M.
,
Conway
,
G.D.
,
Peroutka
,
R.J.
and
Buzza
,
M.S.
(
2016
)
Membrane-anchored proteases in endothelial cell biology
.
Curr. Opin. Hematol.
23
,
243
252
3
Martin
,
C.E.
and
List
,
K.
(
2019
)
Cell surface-anchored serine proteases in cancer progression and metastasis
.
Cancer Metastasis Rev.
38
,
357
387
4
Netzel-Arnett
,
S.
,
Hooper
,
J.D.
,
Szabo
,
R.
,
Madison
,
E.L.
,
Quigley
,
J.P.
,
Bugge
,
T.H.
et al (
2003
)
Membrane anchored serine proteases: a rapidly expanding group of cell surface proteolytic enzymes with potential roles in cancer
.
Cancer Metastasis Rev.
22
,
237
258
5
Friis
,
S.
,
Madsen
,
D.H.
and
Bugge
,
T.H.
(
2016
)
Distinct developmental functions of prostasin (CAP1/PRSS8) zymogen and activated prostasin
.
J. Biol. Chem.
291
,
2577
2582
6
Friis
,
S.
,
Tadeo
,
D.
,
Le-Gall
,
S.M.
,
Jurgensen
,
H.J.
,
Sales
,
K.U.
,
Camerer
,
E.
et al (
2017
)
Matriptase zymogen supports epithelial development, homeostasis and regeneration
.
BMC Biol.
15
,
46
7
Marchiando
,
A.M.
,
Graham
,
W.V.
and
Turner
,
J.R.
(
2010
)
Epithelial barriers in homeostasis and disease
.
Annu. Rev. Pathol.
5
,
119
144
8
Garcia
,
M.A.
,
Nelson
,
W.J.
and
Chavez
,
N.
(
2018
)
Cell-cell junctions organize structural and signaling networks
.
Cold Spring Harb. Perspect. Biol.
10
,
a029181
9
Cohen
,
E.
,
Talmon
,
A.
,
Faff
,
O.
,
Bacher
,
A.
and
Ben-Shaul
,
Y.
(
1985
)
Formation of tight junctions in epithelial cells. I. Induction by proteases in a human colon carcinoma cell line
.
Exp. Cell Res.
156
,
103
116
10
Ronaghan
,
N.J.
,
Shang
,
J.
,
Iablokov
,
V.
,
Zaheer
,
R.
,
Colarusso
,
P.
,
Dion
,
S.
et al (
2016
)
The serine protease-mediated increase in intestinal epithelial barrier function is dependent on occludin and requires an intact tight junction
.
Am. J. Physiol. Gastrointest. Liver Physiol.
311
,
G466
G479
11
List
,
K.
,
Hobson
,
J.P.
,
Molinolo
,
A.
and
Bugge
,
T.H.
(
2007
)
Co-localization of the channel activating protease prostasin/(CAP1/PRSS8) with its candidate activator, matriptase
.
J. Cell. Physiol.
213
,
237
245
12
List
,
K.
,
Haudenschild
,
C.C.
,
Szabo
,
R.
,
Chen
,
W.
,
Wahl
,
S.M.
,
Swaim
,
W.
et al (
2002
)
Matriptase/MT-SP1 is required for postnatal survival, epidermal barrier function, hair follicle development, and thymic homeostasis
.
Oncogene
21
,
3765
3779
13
List
,
K.
,
Kosa
,
P.
,
Szabo
,
R.
,
Bey
,
A.L.
,
Wang
,
C.B.
,
Molinolo
,
A.
et al (
2009
)
Epithelial integrity is maintained by a matriptase-dependent proteolytic pathway
.
Am. J. Pathol.
175
,
1453
1463
14
Leyvraz
,
C.
,
Charles
,
R.P.
,
Rubera
,
I.
,
Guitard
,
M.
,
Rotman
,
S.
,
Breiden
,
B.
et al (
2005
)
The epidermal barrier function is dependent on the serine protease CAP1/Prss8
.
J. Cell. Biol.
170
,
487
496
15
Peters
,
D.E.
,
Szabo
,
R.
,
Friis
,
S.
,
Shylo
,
N.A.
,
Uzzun Sales
,
K.
,
Holmbeck
,
K.
et al (
2014
)
The membrane-anchored serine protease prostasin (CAP1/PRSS8) supports epidermal development and postnatal homeostasis independent of its enzymatic activity
.
J. Biol. Chem.
289
,
14740
14749
16
Yin
,
H.
,
Kosa
,
P.
,
Liu
,
X.
,
Swaim
,
W.D.
,
Lai
,
Z.
,
Cabrera-Perez
,
J.
et al (
2014
)
Matriptase deletion initiates a Sjogren's syndrome-like disease in mice
.
PLoS One
9
,
e82852
17
Szabo
,
R.
,
Peters
,
D.E.
,
Kosa
,
P.
,
Camerer
,
E.
and
Bugge
,
T.H.
(
2014
)
Regulation of feto-maternal barrier by matriptase- and PAR-2-mediated signaling is required for placental morphogenesis and mouse embryonic survival
.
PLoS Genet.
10
,
e1004470
18
Frateschi
,
S.
,
Keppner
,
A.
,
Malsure
,
S.
,
Iwaszkiewicz
,
J.
,
Sergi
,
C.
,
Merillat
,
A.M.
et al (
2012
)
Mutations of the serine protease CAP1/Prss8 lead to reduced embryonic viability, skin defects, and decreased ENaC activity
.
Am. J. Pathol.
181
,
605
615
19
Hummler
,
E.
,
Dousse
,
A.
,
Rieder
,
A.
,
Stehle
,
J.C.
,
Rubera
,
I.
,
Osterheld
,
M.C.
et al (
2013
)
The channel-activating protease CAP1/Prss8 is required for placental labyrinth maturation
.
PLoS One
8
,
e55796
20
Malsure
,
S.
,
Wang
,
Q.
,
Charles
,
R.P.
,
Sergi
,
C.
,
Perrier
,
R.
,
Christensen
,
B.M.
et al (
2014
)
Colon-specific deletion of epithelial sodium channel causes sodium loss and aldosterone resistance
.
J. Am. Soc. Nephrol.
25
,
1453
1464
21
Keppner
,
A.
,
Malsure
,
S.
,
Nobile
,
A.
,
Auberson
,
M.
,
Bonny
,
O.
and
Hummler
,
E.
(
2016
)
Altered prostasin (CAP1/Prss8) expression favors inflammation and tissue remodeling in DSS-induced colitis
.
Inflamm. Bowel Dis.
22
,
2824
2839
22
Bauer
,
A.
,
Hiemesch
,
T.
,
Jagannathan
,
V.
,
Neuditschko
,
M.
,
Bachmann
,
I.
,
Rieder
,
S.
et al (
2017
)
A nonsense variant in the ST14 Gene in Akhal-Teke Horses with Naked Foal Syndrome
.
G3 (Bethesda)
7
,
1315
1321
23
Basel-Vanagaite
,
L.
,
Attia
,
R.
,
Ishida-Yamamoto
,
A.
,
Rainshtein
,
L.
,
Ben Amitai
,
D.
,
Lurie
,
R.
et al (
2007
)
Autosomal recessive ichthyosis with hypotrichosis caused by a mutation in ST14, encoding type II transmembrane serine protease matriptase
.
Am. J. Hum. Genet.
80
,
467
477
24
Drees
,
L.
,
Konigsmann
,
T.
,
Jaspers
,
M.H.J.
,
Pflanz
,
R.
,
Riedel
,
D.
and
Schuh
,
R.
(
2019
)
Conserved function of the matriptase–prostasin proteolytic cascade during epithelial morphogenesis
.
PLoS Genet.
15
25
Buzza
,
M.S.
,
Netzel-Arnett
,
S.
,
Shea-Donohue
,
T.
,
Zhao
,
A.
,
Lin
,
C.Y.
,
List
,
K.
et al (
2010
)
Membrane-anchored serine protease matriptase regulates epithelial barrier formation and permeability in the intestine
.
Proc. Natl. Acad. Sci. U.S.A.
107
,
4200
4205
26
Gray
,
K.
,
Elghadban
,
S.
,
Thongyoo
,
P.
,
Owen
,
K.A.
,
Szabo
,
R.
,
Bugge
,
T.H.
et al (
2014
)
Potent and specific inhibition of the biological activity of the type-II transmembrane serine protease matriptase by the cyclic microprotein MCoTI-II
.
Thromb. Haemost.
112
,
402
411
27
Kosa
,
P.
,
Szabo
,
R.
,
Molinolo
,
A.A.
and
Bugge
,
T.H.
(
2012
)
Suppression of tumorigenicity-14, encoding matriptase, is a critical suppressor of colitis and colitis-associated colon carcinogenesis
.
Oncogene
31
,
3679
3695
28
Szabo
,
R.
,
Rasmussen
,
A.L.
,
Moyer
,
A.B.
,
Kosa
,
P.
,
Schafer
,
J.M.
,
Molinolo
,
A.A.
et al (
2011
)
c-Met-induced epithelial carcinogenesis is initiated by the serine protease matriptase
.
Oncogene
30
,
2003
2016
29
Sales
,
K.U.
,
Friis
,
S.
,
Konkel
,
J.E.
,
Godiksen
,
S.
,
Hatakeyama
,
M.
,
Hansen
,
K.K.
et al (
2015
)
Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis
.
Oncogene
34
,
346
356
30
Schepis
,
A.
,
Barker
,
A.
,
Srinivasan
,
Y.
,
Balouch
,
E.
,
Zheng
,
Y.
,
Lam
,
I.
et al (
2018
)
Protease signaling regulates apical cell extrusion, cell contacts, and proliferation in epithelia
.
J. Cell. Biol.
217
,
1097
1112
31
Frateschi
,
S.
,
Camerer
,
E.
,
Crisante
,
G.
,
Rieser
,
S.
,
Membrez
,
M.
,
Charles
,
R.P.
et al (
2011
)
PAR2 absence completely rescues inflammation and ichthyosis caused by altered CAP1/Prss8 expression in mouse skin
.
Nat. Commun.
2
,
161
32
Kleyman
,
T.R.
and
Eaton
,
D.C.
(
2020
)
Regulating ENaC's gate
.
Am. J. Physiol. Cell Physiol.
318
,
C150
CC62
33
Adams
,
M.N.
,
Ramachandran
,
R.
,
Yau
,
M.K.
,
Suen
,
J.Y.
,
Fairlie
,
D.P.
,
Hollenberg
,
M.D.
et al (
2011
)
Structure, function and pathophysiology of protease activated receptors
.
Pharmacol. Ther.
130
,
248
282
34
Hummler
,
E.
,
Barker
,
P.
,
Gatzy
,
J.
,
Beermann
,
F.
,
Verdumo
,
C.
,
Schmidt
,
A.
et al (
1996
)
Early death due to defective neonatal lung liquid clearance in alpha-ENaC-deficient mice
.
Nat. Genet.
12
,
325
328
35
Schmidt
,
C.
,
Bladt
,
F.
,
Goedecke
,
S.
,
Brinkmann
,
V.
,
Zschiesche
,
W.
,
Sharpe
,
M.
et al (
1995
)
Scatter factor/hepatocyte growth factor is essential for liver development
.
Nature
373
,
699
702
36
Uehara
,
Y.
,
Minowa
,
O.
,
Mori
,
C.
,
Shiota
,
K.
,
Kuno
,
J.
,
Noda
,
T.
et al (
1995
)
Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor
.
Nature
373
,
702
705
37
Sivagnanam
,
M.
,
Mueller
,
J.L.
,
Lee
,
H.
,
Chen
,
Z.
,
Nelson
,
S.F.
,
Turner
,
D.
et al (
2008
)
Identification of EpCAM as the gene for congenital tufting enteropathy
.
Gastroenterology
135
,
429
437
38
Wu
,
C.J.
,
Feng
,
X.
,
Lu
,
M.
,
Morimura
,
S.
and
Udey
,
M.C.
(
2017
)
Matriptase-mediated cleavage of EpCAM destabilizes claudins and dysregulates intestinal epithelial homeostasis
.
J. Clin. Invest.
127
,
623
634
39
Heinz-Erian
,
P.
,
Muller
,
T.
,
Krabichler
,
B.
,
Schranz
,
M.
,
Becker
,
C.
,
Ruschendorf
,
F.
et al (
2009
)
Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea
.
Am. J. Hum. Genet.
84
,
188
196
40
Szabo
,
R.
and
Bugge
,
T.H.
(
2018
)
Loss of HAI-2 in mice with decreased prostasin activity leads to an early-onset intestinal failure resembling congenital tufting enteropathy
.
PLoS One
13
,
e0194660
41
Kawaguchi
,
M.
,
Yamamoto
,
K.
,
Takeda
,
N.
,
Fukushima
,
T.
,
Yamashita
,
F.
,
Sato
,
K.
et al (
2019
)
Hepatocyte growth factor activator inhibitor-2 stabilizes Epcam and maintains epithelial organization in the mouse intestine
.
Commun. Biol.
2
,
11
42
Szabo
,
R.
,
Callies
,
L.K.
and
Bugge
,
T.H.
(
2019
)
Matriptase drives early-onset intestinal failure in a mouse model of congenital tufting enteropathy
.
Development
146
,
dev183392
43
Kim
,
D.R.
,
Sharmin
,
S.
,
Inoue
,
M.
and
Kido
,
H.
(
2001
)
Cloning and expression of novel mosaic serine proteases with and without a transmembrane domain from human lung
.
Biochim. Biophys. Acta
1518
,
204
209
44
Madsen
,
D.H.
,
Szabo
,
R.
,
Molinolo
,
A.A.
and
Bugge
,
T.H.
(
2014
)
TMPRSS13 deficiency impairs stratum corneum formation and epidermal barrier acquisition
.
Biochem. J.
461
,
487
495
45
Sales
,
K.U.
,
Hobson
,
J.P.
,
Wagenaar-Miller
,
R.
,
Szabo
,
R.
,
Rasmussen
,
A.L.
,
Bey
,
A.
et al (
2011
)
Expression and genetic loss of function analysis of the HAT/DESC cluster proteases TMPRSS11A and HAT
.
PLoS One
6
,
e23261
46
Fagerberg
,
L.
,
Hallstrom
,
B.M.
,
Oksvold
,
P.
,
Kampf
,
C.
,
Djureinovic
,
D.
,
Odeberg
,
J.
et al (
2014
)
Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics
.
Mol. Cell. Proteomics
13
,
397
406
47
Zhang
,
Z.
,
Hu
,
Y.
,
Yan
,
R.
,
Dong
,
L.
,
Jiang
,
Y.
,
Zhou
,
Z.
et al (
2017
)
The transmembrane serine protease HAT-like 4 is important for epidermal barrier function to prevent body fluid loss
.
Sci. Rep.
7
,
45262
48
Callies
,
L.K.
,
Tadeo
,
D.
,
Simper
,
J.
,
Bugge
,
T.H.
and
Szabo
,
R.
(
2019
)
Iterative, multiplexed CRISPR-mediated gene editing for functional analysis of complex protease gene clusters
.
J. Biol. Chem.
294
,
15987
15996
49
Guipponi
,
M.
,
Vuagniaux
,
G.
,
Wattenhofer
,
M.
,
Shibuya
,
K.
,
Vazquez
,
M.
,
Dougherty
,
L.
et al (
2002
)
The transmembrane serine protease (TMPRSS3) mutated in deafness DFNB8/10 activates the epithelial sodium channel (ENaC) in vitro
.
Hum. Mol. Genet.
11
,
2829
2836
50
Gaillard
,
E.A.
,
Kota
,
P.
,
Gentzsch
,
M.
,
Dokholyan
,
N.V.
,
Stutts
,
M.J.
and
Tarran
,
R.
(
2010
)
Regulation of the epithelial Na+ channel and airway surface liquid volume by serine proteases
.
Pflugers Arch.
460
,
1
17
51
Planes
,
C.
,
Randrianarison
,
N.H.
,
Charles
,
R.P.
,
Frateschi
,
S.
,
Cluzeaud
,
F.
,
Vuagniaux
,
G.
et al (
2010
)
ENaC-mediated alveolar fluid clearance and lung fluid balance depend on the channel-activating protease 1
.
EMBO Mol. Med.
2
,
26
37
52
Valero-Jimenez
,
A.
,
Zuniga
,
J.
,
Cisneros
,
J.
,
Becerril
,
C.
,
Salgado
,
A.
,
Checa
,
M.
et al (
2018
)
Transmembrane protease, serine 4 (TMPRSS4) is upregulated in IPF lungs and increases the fibrotic response in bleomycin-induced lung injury
.
PLoS One
13
53
Bardou
,
O.
,
Menou
,
A.
,
Francois
,
C.
,
Duitman
,
J.W.
,
von der Thusen
,
J.H.
,
Borie
,
R.
et al (
2016
)
Membrane-anchored serine protease matriptase is a trigger of pulmonary fibrogenesis
.
Am. J. Respir. Crit. Care Med.
193
,
847
860
54
Coote
,
K.
,
Atherton-Watson
,
H.C.
,
Sugar
,
R.
,
Young
,
A.
,
MacKenzie-Beevor
,
A.
,
Gosling
,
M.
et al (
2009
)
Camostat attenuates airway epithelial sodium channel function in vivo through the inhibition of a channel-activating protease
.
J. Pharmacol. Exp. Ther.
329
,
764
774
55
Reihill
,
J.A.
,
Walker
,
B.
,
Hamilton
,
R.A.
,
Ferguson
,
T.E.
,
Elborn
,
J.S.
,
Stutts
,
M.J.
et al (
2016
)
Inhibition of protease-epithelial sodium channel signaling improves mucociliary function in cystic fibrosis airways
.
Am. J. Respir. Crit. Care Med.
194
,
701
710
56
Rossier
,
B.C.
,
Staub
,
O.
and
Hummler
,
E.
(
2013
)
Genetic dissection of sodium and potassium transport along the aldosterone-sensitive distal nephron: importance in the control of blood pressure and hypertension
.
FEBS Lett.
587
,
1929
1941
57
Bohnert
,
B.N.
,
Menacher
,
M.
,
Janessa
,
A.
,
Worn
,
M.
,
Schork
,
A.
,
Daiminger
,
S.
et al (
2018
)
Aprotinin prevents proteolytic epithelial sodium channel (ENaC) activation and volume retention in nephrotic syndrome
.
Kidney Int.
93
,
159
172
58
Maekawa
,
A.
,
Kakizoe
,
Y.
,
Miyoshi
,
T.
,
Wakida
,
N.
,
Ko
,
T.
,
Shiraishi
,
N.
et al (
2009
)
Camostat mesilate inhibits prostasin activity and reduces blood pressure and renal injury in salt-sensitive hypertension
.
J. Hypertens.
27
,
181
189
59
Zhou
,
Y.
and
Wu
,
Q.
(
2014
)
Corin in natriuretic peptide processing and hypertension
.
Curr. Hypertens Rep.
16
,
415
60
Wang
,
W.
,
Shen
,
J.
,
Cui
,
Y.
,
Jiang
,
J.
,
Chen
,
S.
,
Peng
,
J.
et al (
2012
)
Impaired sodium excretion and salt-sensitive hypertension in corin-deficient mice
.
Kidney Int.
82
,
26
33
61
Chan
,
J.C.
,
Knudson
,
O.
,
Wu
,
F.
,
Morser
,
J.
,
Dole
,
W.P.
and
Wu
,
Q.
(
2005
)
Hypertension in mice lacking the proatrial natriuretic peptide convertase corin
.
Proc. Natl. Acad. Sci. U.S.A.
102
,
785
790
62
Cui
,
Y.
,
Wang
,
W.
,
Dong
,
N.
,
Lou
,
J.
,
Srinivasan
,
D.K.
,
Cheng
,
W.
et al (
2012
)
Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy
.
Nature
484
,
246
250
63
Polzin
,
D.
,
Kaminski
,
H.J.
,
Kastner
,
C.
,
Wang
,
W.
,
Kramer
,
S.
,
Gambaryan
,
S.
et al (
2010
)
Decreased renal corin expression contributes to sodium retention in proteinuric kidney diseases
.
Kidney Int.
78
,
650
659
64
Theilig
,
F.
and
Wu
,
Q.
(
2015
)
ANP-induced signaling cascade and its implications in renal pathophysiology
.
Am. J. Physiol. Renal. Physiol.
308
,
F1047
F1055
65
Guo
,
L.J.
,
Alli
,
A.A.
,
Eaton
,
D.C.
and
Bao
,
H.F.
(
2013
)
ENac is regulated by natriuretic peptide receptor-dependent cGMP signaling
.
Am. J. Physiol. Renal. Physiol.
304
,
F930
F937
66
Yan
,
W.
,
Sheng
,
N.
,
Seto
,
M.
,
Morser
,
J.
and
Wu
,
Q.
(
1999
)
Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart
.
J. Biol. Chem.
274
,
14926
14935
67
Kaitu'u-Lino
,
T.J.
,
Ye
,
L.
,
Tuohey
,
L.
,
Dimitriadis
,
E.
,
Bulmer
,
J.
,
Rogers
,
P.
et al (
2013
)
Corin, an enzyme with a putative role in spiral artery remodeling, is up-regulated in late secretory endometrium and first trimester decidua
.
Hum. Reprod.
28
,
1172
1180
68
Red-Horse
,
K.
,
Zhou
,
Y.
,
Genbacev
,
O.
,
Prakobphol
,
A.
,
Foulk
,
R.
,
McMaster
,
M.
et al (
2004
)
Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface
.
J. Clin. Invest.
114
,
744
754
69
Pijnenborg
,
R.
,
Vercruysse
,
L.
and
Hanssens
,
M.
(
2006
)
The uterine spiral arteries in human pregnancy: facts and controversies
.
Placenta
27
,
939
958
70
Baird
,
R.C.
,
Li
,
S.
,
Wang
,
H.
,
Naga Prasad
,
S.V.
,
Majdalany
,
D.
,
Perni
,
U.
et al (
2019
)
Pregnancy-associated cardiac hypertrophy in corin-deficient mice: observations in a transgenic model of preeclampsia
.
Can. J. Cardiol.
35
,
68
76
71
Brunati
,
M.
,
Perucca
,
S.
,
Han
,
L.
,
Cattaneo
,
A.
,
Consolato
,
F.
,
Andolfo
,
A.
et al (
2015
)
The serine protease hepsin mediates urinary secretion and polymerisation of zona pellucida domain protein uromodulin
.
eLife
4
,
e08887
72
Olinger
,
E.
,
Lake
,
J.
,
Sheehan
,
S.
,
Schiano
,
G.
,
Takata
,
T.
,
Tokonami
,
N.
et al (
2019
)
Hepsin-mediated processing of uromodulin is crucial for salt-sensitivity and thick ascending limb homeostasis
.
Sci. Rep.
9
,
12287
73
Hart
,
T.C.
,
Gorry
,
M.C.
,
Hart
,
P.S.
,
Woodard
,
A.S.
,
Shihabi
,
Z.
,
Sandhu
,
J.
et al (
2002
)
Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy
.
J. Med. Genet.
39
,
882
892
74
Padmanabhan
,
S.
,
Melander
,
O.
,
Johnson
,
T.
,
Di Blasio
,
A.M.
,
Lee
,
W.K.
,
Gentilini
,
D.
et al (
2010
)
Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension
.
PLoS Genet.
6
,
e1001177
75
Gudbjartsson
,
D.F.
,
Holm
,
H.
,
Indridason
,
O.S.
,
Thorleifsson
,
G.
,
Edvardsson
,
V.
,
Sulem
,
P.
et al (
2010
)
Association of variants at UMOD with chronic kidney disease and kidney stones-role of age and comorbid diseases
.
PLoS Genet.
6
,
e1001039
76
Mutig
,
K.
,
Kahl
,
T.
,
Saritas
,
T.
,
Godes
,
M.
,
Persson
,
P.
,
Bates
,
J.
et al (
2011
)
Activation of the bumetanide-sensitive Na+,K+,2Cl- cotransporter (NKCC2) is facilitated by Tamm–Horsfall protein in a chloride-sensitive manner
.
J. Biol. Chem.
286
,
30200
30210
77
Renigunta
,
A.
,
Renigunta
,
V.
,
Saritas
,
T.
,
Decher
,
N.
,
Mutig
,
K.
and
Waldegger
,
S.
(
2011
)
Tamm–Horsfall glycoprotein interacts with renal outer medullary potassium channel ROMK2 and regulates its function
.
J. Biol. Chem.
286
,
2224
2235
78
Mittal
,
R.
,
Aranke
,
M.
,
Debs
,
L.H.
,
Nguyen
,
D.
,
Patel
,
A.P.
,
Grati
,
M.
et al (
2017
)
Indispensable role of ion channels and transporters in the auditory system
.
J. Cell. Physiol.
232
,
743
758
79
Guipponi
,
M.
,
Antonarakis
,
S.E.
and
Scott
,
H.S.
(
2008
)
TMPRSS3, a type II transmembrane serine protease mutated in non-syndromic autosomal recessive deafness
.
Front. Biosci.
13
,
1557
1567
80
Fasquelle
,
L.
,
Scott
,
H.S.
,
Lenoir
,
M.
,
Wang
,
J.
,
Rebillard
,
G.
,
Gaboyard
,
S.
et al (
2011
)
Tmprss3, a transmembrane serine protease deficient in human DFNB8/10 deafness, is critical for cochlear hair cell survival at the onset of hearing
.
J. Biol. Chem.
286
,
17383
17397
81
Molina
,
L.
,
Fasquelle
,
L.
,
Nouvian
,
R.
,
Salvetat
,
N.
,
Scott
,
H.S.
,
Guipponi
,
M.
et al (
2013
)
Tmprss3 loss of function impairs cochlear inner hair cell Kcnma1 channel membrane expression
.
Hum. Mol. Genet.
22
,
1289
1299
82
Tang
,
P.C.
,
Alex
,
A.L.
,
Nie
,
J.
,
Lee
,
J.
,
Roth
,
A.A.
,
Booth
,
K.T.
et al (
2019
)
Defective Tmprss3-associated hair cell degeneration in inner ear organoids
.
Stem Cell Rep.
13
,
147
162
83
Peters
,
T.A.
,
Levtchenko
,
E.
,
Cremers
,
C.W.
,
Curfs
,
J.H.
and
Monnens
,
L.A.
(
2006
)
No evidence of hearing loss in pseudohypoaldosteronism type 1 patients
.
Acta Otolaryngol.
126
,
237
239
84
Guipponi
,
M.
,
Tan
,
J.
,
Cannon
,
P.Z.
,
Donley
,
L.
,
Crewther
,
P.
,
Clarke
,
M.
et al (
2007
)
Mice deficient for the type II transmembrane serine protease, TMPRSS1/hepsin, exhibit profound hearing loss
.
Am. J. Pathol.
171
,
608
616
85
Ray
,
R.P.
,
Matamoro-Vidal
,
A.
,
Ribeiro
,
P.S.
,
Tapon
,
N.
,
Houle
,
D.
,
Salazar-Ciudad
,
I.
et al (
2015
)
Patterned anchorage to the apical extracellular matrix defines tissue shape in the developing appendages of Drosophila
.
Dev. Cell
34
,
310
322
86
Diaz-de-la-Loza
,
M.D.
,
Ray
,
R.P.
,
Ganguly
,
P.S.
,
Alt
,
S.
,
Davis
,
J.R.
,
Hoppe
,
A.
et al (
2018
)
Apical and basal matrix remodeling control epithelial morphogenesis
.
Dev. Cell
46
,
23
39.e5
87
Bertram
,
S.
,
Glowacka
,
I.
,
Blazejewska
,
P.
,
Soilleux
,
E.
,
Allen
,
P.
,
Danisch
,
S.
et al (
2010
)
TMPRSS2 and TMPRSS4 facilitate trypsin-independent spread of influenza virus in Caco-2 cells
.
J. Virol.
84
,
10016
10025
88
Shin
,
W.J.
and
Seong
,
B.L.
(
2017
)
Type II transmembrane serine proteases as potential target for anti-influenza drug discovery
.
Expert Opin. Drug Discov.
12
,
1139
1152
89
Bottcher-Friebertshauser
,
E.
,
Klenk
,
H.D.
and
Garten
,
W.
(
2013
)
Activation of influenza viruses by proteases from host cells and bacteria in the human airway epithelium
.
Pathog. Dis.
69
,
87
100
90
Cheng
,
Z.
,
Zhou
,
J.
,
To
,
K.K.
,
Chu
,
H.
,
Li
,
C.
,
Wang
,
D.
et al (
2015
)
Identification of TMPRSS2 as a susceptibility gene for severe 2009 pandemic A(H1N1) influenza and A(H7N9) influenza
.
J. Infect. Dis.
212
,
1214
1221
91
Keppner
,
A.
,
Andreasen
,
D.
,
Merillat
,
A.M.
,
Bapst
,
J.
,
Ansermet
,
C.
,
Wang
,
Q.
et al (
2015
)
Epithelial sodium channel-mediated sodium transport is not dependent on the membrane-bound serine protease CAP2/Tmprss4
.
PLoS One
10
,
e0135224
92
Lambertz
,
R.L.O.
,
Gerhauser
,
I.
,
Nehlmeier
,
I.
,
Leist
,
S.R.
,
Kollmus
,
H.
,
Pohlmann
,
S.
et al (
2019
)
Tmprss2 knock-out mice are resistant to H10 influenza A virus pathogenesis
.
J. Gen. Virol.
100
,
1073
1078
93
Kuhn
,
N.
,
Bergmann
,
S.
,
Kosterke
,
N.
,
Lambertz
,
R.L.O.
,
Keppner
,
A.
,
van den Brand
,
J.M.A.
et al (
2016
)
The proteolytic activation of (H3N2) influenza A virus hemagglutinin is facilitated by different type II transmembrane serine proteases
.
J. Virol.
90
,
4298
4307
94
Sakai
,
K.
,
Ami
,
Y.
,
Tahara
,
M.
,
Kubota
,
T.
,
Anraku
,
M.
,
Abe
,
M.
et al (
2014
)
The host protease TMPRSS2 plays a major role in in vivo replication of emerging H7N9 and seasonal influenza viruses
.
J. Virol.
88
,
5608
5616
95
Hatesuer
,
B.
,
Bertram
,
S.
,
Mehnert
,
N.
,
Bahgat
,
M.M.
,
Nelson
,
P.S.
,
Pohlmann
,
S.
et al (
2013
)
Tmprss2 is essential for influenza H1N1 virus pathogenesis in mice
.
PLoS Pathog.
9
,
e1003774
96
Bertram
,
S.
,
Glowacka
,
I.
,
Muller
,
M.A.
,
Lavender
,
H.
,
Gnirss
,
K.
,
Nehlmeier
,
I.
et al (
2011
)
Cleavage and activation of the severe acute respiratory syndrome coronavirus spike protein by human airway trypsin-like protease
.
J. Virol.
85
,
13363
13372
97
Abe
,
M.
,
Tahara
,
M.
,
Sakai
,
K.
,
Yamaguchi
,
H.
,
Kanou
,
K.
,
Shirato
,
K.
et al (
2013
)
TMPRSS2 is an activating protease for respiratory parainfluenza viruses
.
J. Virol.
87
,
11930
5
98
Zmora
,
P.
,
Blazejewska
,
P.
,
Moldenhauer
,
A.S.
,
Welsch
,
K.
,
Nehlmeier
,
I.
,
Wu
,
Q.
et al (
2014
)
DESC1 and MSPL activate influenza A viruses and emerging coronaviruses for host cell entry
.
J. Virol.
88
,
12087
12097
99
Zmora
,
P.
,
Hoffmann
,
M.
,
Kollmus
,
H.
,
Moldenhauer
,
A.S.
,
Danov
,
O.
,
Braun
,
A.
et al (
2018
)
TMPRSS11A activates the influenza A virus hemagglutinin and the MERS coronavirus spike protein and is insensitive against blockade by HAI-1
.
J. Biol. Chem.
293
,
13863
13873
100
Reinke
,
L.M.
,
Spiegel
,
M.
,
Plegge
,
T.
,
Hartleib
,
A.
,
Nehlmeier
,
I.
,
Gierer
,
S.
et al (
2017
)
Different residues in the SARS-CoV spike protein determine cleavage and activation by the host cell protease TMPRSS2
.
PLoS One
12
,
e0179177
101
Kam
,
Y.W.
,
Okumura
,
Y.
,
Kido
,
H.
,
Ng
,
L.F.
,
Bruzzone
,
R.
and
Altmeyer
,
R.
(
2009
)
Cleavage of the SARS coronavirus spike glycoprotein by airway proteases enhances virus entry into human bronchial epithelial cells in vitro
.
PLoS One
4
,
e7870
102
Straus
,
M.R.
,
Kinder
,
J.T.
,
Segall
,
M.
,
Dutch
,
R.E.
and
Whittaker
,
G.R.
(
2020
)
SPINT2 inhibits proteases involved in activation of both influenza viruses and metapneumoviruses
.
Virology
543
,
43
53