Receptor signalling events including those initiated following activation of cytokine and growth factor receptors and the well-characterised death receptors (tumour necrosis factor receptor, type 1, FasR and TRAIL-R1/2) are initiated at the cell surface through the recruitment and formation of intracellular multiprotein signalling complexes that activate divergent signalling pathways. Over the past decade, research studies reveal that many of these receptor-initiated signalling events involve the sequential proteolysis of specific receptors by membrane-bound proteases and the γ-secretase protease complexes. Proteolysis enables the liberation of soluble receptor ectodomains and the generation of intracellular receptor cytoplasmic domain fragments. The combined and sequential enzymatic activity has been defined as regulated intramembrane proteolysis and is now a fundamental signal transduction process involved in the termination or propagation of receptor signalling events. In this review, we discuss emerging evidence for a role of the γ-secretase protease complexes and regulated intramembrane proteolysis in cell- and immune-signalling pathways.

Introduction

Our understanding of the regulatory mechanisms that control how cell surface receptors transduce downstream signals has, in recent years, increased in both complexity and diversity. One such mechanism, termed regulated intramembrane proteolysis (RIP), is an evolutionarily conserved and fundamental signal transduction process involves the sequential proteolytic liberation of extracellular and/or intracellular soluble fragments [14]. Highly conserved from bacteria to humans, RIP has many proposed roles in cellular function including proliferation [5], differentiation [1], protein degradation [6], cell adhesion [7], lipid metabolism, transcriptional regulation and mitophagy [8].

Regulated intramembrane proteolysis — classification and components

RIP is predominantly a progressive two-step proteolytic process (Figure 1), initiated following the cleavage of a single-span transmembrane protein with type I or type II orientation. The initial cleavage event, which is referred to as ectodomain shedding, is itself a tightly regulated process, in which the extracellular domains of integral membrane proteins are proteolytically cleaved and thus solubilised [9]. A broad range of stimuli can activate ectodomain shedding, either by up-regulating the activity of specific proteases or by stimulating the shedding of specific protein ectodomains [10]. The proteases that carry out the process of ectodomain shedding, collectively termed ‘sheddases’, include the metalloproteinase disintegrin family (ADAMs), the matrix metalloproteinase family, neutrophil-derived proteases and the aspartyl proteases BACE1 and BACE2 (β-site APP-cleaving enzymes) [2,11]. Following ectodomain shedding, the remaining membrane-embedded fragment is cleaved within its transmembrane domain by a family of proteins known as the intramembrane-cleaving proteases (iCliPs) [12]. Cleavage results in the release of a soluble extracellular fragment and cytosolic intracellular domains (ICD) from the membrane. Four main families of iCliPs exist in humans: the zinc metalloproteases (of which S2P is the only known member), aspartyl proteases that include the presenilin [Presenilin 1 (PS1) or Presenilin 2 (PS2)]-contained γ-secretase protease complex, serine or rhomboid proteases and the recently identified glutamate protease [13].

Schematic depicting regulated intramembrane proteolysis.

Figure 1.
Schematic depicting regulated intramembrane proteolysis.

Regulated intramembrane proteolysis is defined as the sequential proteolysis of an integral membrane protein with type I or type II orientation, involving iCliPs. First, cleavage within the substrate extracellular domain by proteases collectively termed ‘sheddases’ including ADAM proteases and BACE (β-secretase), release the soluble ectodomain and generate a membrane-bound fragment, which becomes a substrate for further cleavage by members of the iCliP family of proteases. The iCliPs are responsible for the second cleavage event and hydrolysis of peptide bonds in the hydrophobic lipid bilayer of many transmembrane proteins and the release of soluble peptides and an ICD. The ICD can be rapidly degraded or possess substrate-specific biological activities, including roles as a cytosolic effector in cell signalling and nuclear gene transcription.

Figure 1.
Schematic depicting regulated intramembrane proteolysis.

Regulated intramembrane proteolysis is defined as the sequential proteolysis of an integral membrane protein with type I or type II orientation, involving iCliPs. First, cleavage within the substrate extracellular domain by proteases collectively termed ‘sheddases’ including ADAM proteases and BACE (β-secretase), release the soluble ectodomain and generate a membrane-bound fragment, which becomes a substrate for further cleavage by members of the iCliP family of proteases. The iCliPs are responsible for the second cleavage event and hydrolysis of peptide bonds in the hydrophobic lipid bilayer of many transmembrane proteins and the release of soluble peptides and an ICD. The ICD can be rapidly degraded or possess substrate-specific biological activities, including roles as a cytosolic effector in cell signalling and nuclear gene transcription.

The γ-secretase proteases (Figure 2) are tetrameric protein complexes consisting of PS1 or PS2, nicastrin, anterior pharynx defective-1 (Aph-1) and presenilin enhancer-2 (Pen-2), reviewed in ref. [14]. The requirement for each of these four integral membrane proteins for γ-secretase activity was verified following genetic ablation or RNAi knockdown of one or the other of the components, as well as by genetic reconstitution of γ-secretase activity in Saccharomyces cerevisiae, which lacks endogenous γ-secretase [15]. All four proteins associate with each other and their co-expression resulted in increased γ-secretase activity in mammalian cells [16], Drosophila and S. cerevisiae, reviewed in refs [14,16,17]. The multiprotein identity of the γ-secretase proteases was subsequently corroborated by several studies reporting the purification of the active γ-secretase protease complexes [1820]. Of these γ-secretase components, several variants exist of the presenilins (PS1 and PS2) and Aph-1 due to multiple genes and to alternative splicing thereof. In all species examined, there are two Psen genes (Psen1 and Psen2); while in humans there are also two Aph-1 genes, Aph-1a and Aph-1b, which are alternatively spliced [21]. Furthermore, in rodents, gene duplication of Aph-1b produces a third gene, Aph-1c [21]. It has now been demonstrated that multiple combinations of the four proteins can exist, depending on which Psen and Aph-1 gene product is included therein, and that γ-secretase complexes have different functions based on their precise cofactor composition since the gene products of Psen and Aph1 are not redundant [2022]. Like other iCliPs, differences in the subcellular localisation of γ-secretase proteases are reflective of their distinct function and substrate specificity [4,2326], discussed in more detail later.

Schematic of the tetrameric γ-secretase protease complex.

Figure 2.
Schematic of the tetrameric γ-secretase protease complex.

The γ-secretase protease complex is composed of four integral membrane proteins: Pen-2, presenilin (PS1 or PS2), nicastrin and Aph-1 (Aph-1a/Aph-1b). Different genes encode Presenilin 1 and presenilin 2, and Aph-1a and Aph-1b, and all subunits can combine to produce at least four distinct protease complexes in humans. Presenilin provides the active site and requires endoproteolysis to produce catalytically active presenilin N-terminal fragment/C-terminal fragment (NTF/CTF) heterodimers.

Figure 2.
Schematic of the tetrameric γ-secretase protease complex.

The γ-secretase protease complex is composed of four integral membrane proteins: Pen-2, presenilin (PS1 or PS2), nicastrin and Aph-1 (Aph-1a/Aph-1b). Different genes encode Presenilin 1 and presenilin 2, and Aph-1a and Aph-1b, and all subunits can combine to produce at least four distinct protease complexes in humans. Presenilin provides the active site and requires endoproteolysis to produce catalytically active presenilin N-terminal fragment/C-terminal fragment (NTF/CTF) heterodimers.

Diversity of RIP substrates and biological functions

To date, in excess of 100 transmembrane protein substrates that undergo RIP have been reported, including growth factors, cytokines, cell adhesion proteins, growth factor and cytokine receptors, viral proteins and signal peptides [4,27,28]. Among the best studied and characterised RIP substrates are functionally important proteins such as amyloid-β precursor protein (APP) [29], Notch [30,31], E-Cadherin [7], tumour necrosis factor-α (TNF-α) [32], interleukin-1 (IL-1) receptor, type I and II (IL-1RI and IL-1RII) [3335], insulin-like growth factor 1 receptor [36], epidermal growth factor [37], ErbB4 [38], p75 neurotrophin receptor (p75NTR) [3941], CD44 [42], triggering receptor expressed on myeloid cells-2 (TREM2) [43] and epithelial cell adhesion molecule (EpCAM) [44] among others, reviewed in ref. [4,27,28]. Given the biological diversity of substrates, it is proposed that RIP is important for many physiological processes, such as embryonic development, haematopoiesis and normal functioning of the nervous system and the immune system, reviewed in refs [24,4547].

RIP is a sequential proteolytic process resulting in the generation and release of soluble protein fragments that can possess biological activities (Figure 1). For example, the proteolysis and release of membrane-bound growth factors provides for the generation of a soluble signalling molecule that can activate target cells [32,48,49], while ectodomain shedding also liberates cytokines and chemokines from their membrane-bound state, allowing them to regulate immune cell recruitment [9]. For example, TACE (TNF-α-converting enzyme)/ADAM17-mediated ectodomain shedding of TNF-α [50], and ADAM10-mediated shedding of chemokines CXCL16 [51] and CX3CL1 (Fractalkine), results in their liberation and activation. For other substrates, such as the cytokine and growth factor receptors p75NTR, TNF receptor, type 1 (TNFR1), IL-1RI and IL-1RII, it is proposed that ectodomain shedding serves as a means of regulating receptor-mediated signalling, as shedding of the soluble receptor ectodomain reduces cell surface availability of receptors and desensitises cells to further stimulation [33,34,52]. Additionally, because the soluble receptor ectodomain can still bind to circulating ligands, ectodomain shedding also provides a mechanism for regulating the amount of soluble ligand available to bind and signal through membrane-bound receptors. In contrast, the biological significance of the subsequent γ-secretase cleavage and generation of ICD fragments remains less defined [2,53]. From the characterisation of numerous RIP substrates, it is proposed that γ-secretase cleavage of membrane-embedded protein fragments has one of three principal biological functions (Figure 1). First, it is a novel mechanism that enables the nuclear translocation of receptor-derived ICDs and regulation of gene transcription; second, it is a mechanism enabling the removal and degradation of protein fragments from biological membranes, and finally, it may be a mechanism enabling the spatial segregation of biologically distinct signalling pathways initiated by a common receptor.

For some better-characterised RIP substrates, such as Notch, EpCAM and ErbB4, it is the newly generated ICD that possesses biological activity [30,44]. In each case, the Notch ICD (NICD), EpCAM ICD (EpICD) and ErbB4 ICD (E4ICD) translocate to the nucleus and facilitate the transcriptional regulation of target genes (Figure 3). In mammals, there are four Notch receptors (Notch 1–4), which require three proteolytic cleavage steps for canonical Notch receptor signalling. The Notch peptide precursor is first cleaved in the trans-Golgi by furin convertase (S1 cleavage), which produces a heterodimer consisting of an N-terminal extracellular fragment that is accessible to Notch ligands and a C-terminal transmembrane fragment (NEXT). Following ligand binding, a second ADAM-mediated proteolytic event (S2 cleavage) releases the Notch extracellular domain (NECD) from the cell (Figure 3A). Subsequently, γ-secretase cleaves the NEXT fragment (S3 cleavage), generating the transcriptionally active NICD. As NICD enters the nucleus, it displaces co-repressors (CoR) from the transcription factor CSL [CBF 1/Sn(H)/Lag 1]. Upon binding with CSL, NICD forms a ternary complex with Mastermind-like proteins (MAML) and further recruits transcriptional co-activators like cAMP response element-binding protein (CREB)-binding protein (CBP)/P300 to increase the expression of target genes like Hes1, C-myc and Igf1r [31]. In a similar sequence of events, the proteolysis of EpCAM by TACE/ADAM17 results in the generation of a soluble EpCAM extracellular domain (EpEx) and a membrane-bound EpCAM C-terminal fragment (EpCTF), which is subsequently cleaved by the PS2-contained γ-secretase protease generating the biologically active cytosolic EpICD (Figure 3B) [44,54]. In human carcinoma cells, upon cleavage of EpCAM, cytosolic EpICD couples with FHL2 (four-and-a-half LIM domain protein) and Wnt pathway components, β-catenin and Lef-1, forming a nuclear complex that binds DNA at Lef-1 consensus sites, and induces gene transcription of target genes, including c-Myc and cyclin D1, leading to increased cell proliferation and oncogenesis in immunodeficient mice [44]. It is therefore proposed that regulated intramembrane proteolysis of EpCAM by ADAM17 and γ-secretase [55] produces cytosolic EpICD that functions as the oncogenic signal transducer of EpCAM [44]. Similarly, stimulation with neuregulin at the cell surface induces TACE/ADAM17-mediated shedding of the JM-a isoform of the receptor tyrosine kinase ErbB4 [56]. The remaining membrane-embedded ErbB4 fragment is further cleaved within its transmembrane domain by γ-secretase to produce a soluble intracellular dimeric active form of ErbB4, designated E4ICD or s80 [38,5658]. Following presenilin-dependent cleavage of ErbB4 (JM-a), the ternary E4ICD/TAB2/N-CoR complex undergoes nuclear translocation (enabled by the nuclear localisation sequence found in E4ICD) and regulates transcription of several genes (Figure 3C) [57,59,60].

Regulated intramembrane proteolysis and nuclear signalling pathways.

Figure 3.
Regulated intramembrane proteolysis and nuclear signalling pathways.

(A) When Notch binds to its ligand, Notch is cleaved at the S2 site in the juxtamembrane region by the ADAM/TACE protease. Next, the remaining membrane-embedded protein fragment (NEXT) is further cleaved by γ-secretase at the S3 and S4 sites within the transmembrane domain and the NICD is released from the membrane. Then, NICD translocates into the nucleus and binds to the CSL together with MAML. The resultant CSL–NICD–MAML complex removes CoR from CSL transcription factor and recruits a co-activator (CoA), resulting in conversion from repressor to activator. Finally, the complexes of CSL–NICD–MAML CoAs promote transcription of the target genes. (B) EpCAM signalling is induced by cell–cell interaction and RIP. EpCAM is cleaved by ADAM17/TACE leading to the generation of a soluble EpEx and membrane-embedded fragment that is cleaved by PS2-containing γ-secretase to release EpICD, which translocates to the nucleus in a multiprotein complex with FHL2 and β-catenin. Within the nucleus, the EpICD complex interacts with Lef-1 and promoters of genes involved in cell cycle regulation and stemness, including Nanog, Oct4, Klf4, Sox2, Myc and Cyclin D1. (C) Following NGR1-mediated stimulation of ErbB4 and ectodomain shedding by ADAM-17, the membrane-anchored ErbB4 cytoplasmic domain is cleaved by γ-secretase to generate the soluble E4ICD of ErbB4, in complex with TAB2 and the corepressor N-CoR, translocates to the nucleus where it binds to specific promoter elements to regulate the expression of genes. E4ICD interacts with several transcriptional regulators, including Eto2, STAT5, Mdm2 and YAP, to mediate the transcriptional activation or repression of heterologous promoters.

Figure 3.
Regulated intramembrane proteolysis and nuclear signalling pathways.

(A) When Notch binds to its ligand, Notch is cleaved at the S2 site in the juxtamembrane region by the ADAM/TACE protease. Next, the remaining membrane-embedded protein fragment (NEXT) is further cleaved by γ-secretase at the S3 and S4 sites within the transmembrane domain and the NICD is released from the membrane. Then, NICD translocates into the nucleus and binds to the CSL together with MAML. The resultant CSL–NICD–MAML complex removes CoR from CSL transcription factor and recruits a co-activator (CoA), resulting in conversion from repressor to activator. Finally, the complexes of CSL–NICD–MAML CoAs promote transcription of the target genes. (B) EpCAM signalling is induced by cell–cell interaction and RIP. EpCAM is cleaved by ADAM17/TACE leading to the generation of a soluble EpEx and membrane-embedded fragment that is cleaved by PS2-containing γ-secretase to release EpICD, which translocates to the nucleus in a multiprotein complex with FHL2 and β-catenin. Within the nucleus, the EpICD complex interacts with Lef-1 and promoters of genes involved in cell cycle regulation and stemness, including Nanog, Oct4, Klf4, Sox2, Myc and Cyclin D1. (C) Following NGR1-mediated stimulation of ErbB4 and ectodomain shedding by ADAM-17, the membrane-anchored ErbB4 cytoplasmic domain is cleaved by γ-secretase to generate the soluble E4ICD of ErbB4, in complex with TAB2 and the corepressor N-CoR, translocates to the nucleus where it binds to specific promoter elements to regulate the expression of genes. E4ICD interacts with several transcriptional regulators, including Eto2, STAT5, Mdm2 and YAP, to mediate the transcriptional activation or repression of heterologous promoters.

However, for many other RIP substrates, the newly generated ICDs are very short-lived and rapidly degraded, suggesting that certain ICDs do not possess a signalling function. These observations suggest that RIP enables the specific clearance and degradation of the membrane-anchored portion of the processed proteins, which prevents accumulation of large amounts of proteolytic fragments in the membrane. For example, CXCL16 and CX3CL1 are RIP substrates, undergoing sequential cleavage by ADAM10 and γ-secretase [61]. Ectodomain shedding is essential for release of the soluble chemokine, whereas γ-secretase cleavage most likely functions to degrade the remaining membrane-embedded fragments [62]. Similarly, following ligand-stimulated ectodomain shedding of the IL-6 and IL-11 receptors, IL-6R and L-11R, the remaining membrane-embedded fragments are cleaved by γ-secretase [63,64]. However, the failure to readily detect a cytosolic or nuclear IL-6R ICD or IL-11 receptor (IL-11R) ICD led researchers to therefore hypothesise that the potential IL-6R ICD and IL-11R ICD are not involved in nuclear signalling, but instead are rapidly degraded [63,64]. In the case of other substrates, γ-secretase cleavage leads to the generation of a biologically active fragment with a distinct cytosolic (non-nuclear) function. For example, the cadherins primarily facilitate cell–cell adhesion and function in cytosolic signalling pathways via their interaction with α-catenin and β-catenin complexes. Recently, it was shown that following γ-secretase cleavage of N-cadherin, the newly generated N-cadherin ICD (CTF2) has a non-nuclear, cytosolic function [65,66]. The newly generated ICD/CTF2 binds to, and causes the cytoplasmic translocation and proteasomal degradation of the nuclear transcriptional cofactor CBP, thus down-regulating cAMP response element-binding protein (CREB)-mediated transcription [65].

RIP of signalling receptors in the immune system

From the cumulative efforts of several research groups, there is an emerging role for the presenilin proteins and γ-secretase as modulators of the immune system, neuroinflammation and inflammatory disorders. As outlined earlier, several receptors involved in immune signalling, including interleukin IL-1RI, IL-1RII, IL-6R, IL-11R, CX3CL1, CXCL16, MHC class I protein, CD44 and Notch, are γ-secretase substrates (Table 1). Furthermore, PS1 and PS2 interact with several proteins, including TNFR-associated factor 6 (TRAF6) and interleukin receptor-associated kinase 2 (IRAK2) [33], both important intermediates in Toll-like receptor (TLR) and IL-1RI signalling pathways. The link between the presenilins, γ-secretase proteases and the immune system has also been demonstrated by the phenotypic characterisation of in vivo models of presenilin deletion or mutation. Since deletion of Psen1 (encoding PS1) is embryonic lethal [67], transgenic mouse models have been developed to circumvent this effect, including Psen1 null mice that have been rescued with a Psen1 transgene [68] and brain region-specific gene knockout techniques based on the Cre/LoxP system [6971]. In addition, the selective knockout of one or more alleles of the presenilins, with the retention of at least one functional copy, has been used since the early days of presenilin research to define its function with the Psen1+/−Psen2−/− mouse having the most severe reduction in presenilin alleles that permits post-natal survival [72]. The phenotype of Psen1+/−Psen2−/− ‘partial deficient’ mice is normal up to ∼6 months, when the majority of the mice develop skin and autoimmune defects similar to those observed in systemic lupus erythematosus [73]. Thus, Psen1 deficiency is associated with an abnormal immune response and the development of an autoimmune phenotype. The requirement for the presenilins in adaptive immune system function has since been demonstrated in lymphocytes [7476]. Deficiency in presenilins antagonised T-cell homeostasis and signalling [74,75], while presenilin-deficient B-cells were defective in responsiveness to lipopolysaccharide (LPS) and B-cell receptor-induced proliferation and signal transduction [76].

Table 1
List of γ-secretase substrates relevant to immune signalling.
Substrate Immune functions References 
IL-IRI Pro-inflammatory cytokine, IL-1 receptor and signalling [33
IL-1RII IL-1 receptor (antagonist) [34
IL-6R IL-6 receptor [63
IL-11R IL-11 receptor [64
CSF-1 A secreted cytokine that influences haematopoietic stem cells to differentiate into macrophages or other related cell types [151
IFNαR2 Subunit of type 1 IFN-α receptor. [96
TNFR1 Pro-inflammatory cytokine, TNF-α receptor. Pro-inflammatory and cell death signalling pathways [52
TREM2 Triggering receptor expressed on myeloid cells 2 (TREM2). Role in chronic inflammations and may stimulate production of constitutive rather than inflammatory chemokines and cytokines [43
CXC16 Transmembrane chemokine. Scavenger receptor on macrophages induces chemotactic response [62
CX3CL1 Transmembrane chemokine [62
CD43 Cell adhesion molecule. Major glycoproteins of thymocytes and T lymphocytes [152
CD44 Cell adhesion molecule. Cell surface glycoprotein and hyaluronan receptor. [153,154
HLA Human leucocyte antigen (HLA). MHC Class I protein [155
HLA-A2 MHC Class I protein. Immune response, T-cell development, synaptic plasticity and refinement [156
SDC1 Herpes simplex receptor. Receptor for HIV-1, Hepatitis E and human papilloma virus [155
SDC2 Herpes simplex receptor [155
SDC3 Herpes simplex receptor. Receptor for HIV-1 and human papilloma virus (HPV) [155,157,158
NOTCH 1–4 Signalling receptors, cell proliferation and differentiation.
Activated by Epstein Barr Virus 
[159161
CD44 Cell adhesion molecule
Entry receptor for Cryptococcus neoformans, lymphocyte activation, recirculation and homing 
[44
CD46 Receptor for adenoviruses, measles virus, human Herpes Virus 6 (HHV-6), Streptococci and Neisseria. Also cleaved by a protease secreted by Porphyromonas gingivalis. Complement and T-cell regulatory functions [162,163
Desmoglein-2 Adenovirus receptor [155,164
LRP1 Lipoprotein receptor 1. Receptor for rhinovirus, Pseudomonas aeruginosa and exotoxin A. [165
LDLR LDL receptor. Receptor for rhinovirus, Hepatitis C and vesicular stomatitis virus [155
VLDLR Very-low-density-lipoprotein receptor (VLDLR). Receptor for rhinovirus [166
ERBB4 Receptor tyrosine kinase. Receptor for vaccinia and other poxviruses [167
NGFR Neurotrophin receptor. Receptor for rabies virus [41,168
Nectin-1α Immunoglobulin superfamily member that mediates cell–cell adhesion. Receptor for herpes simplex virus (HSV) and pseudorabies virus [169
ADAM10 A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10). Cytotoxin Staphylococcus aureus α-haemolysis-mediated cell injury [170,171
Dystroglycan Receptor for the lymphocytic choriomeningitis, Lassa fever viruses and Mycobacterium leprae (the Leprosy pathogen). [155
Substrate Immune functions References 
IL-IRI Pro-inflammatory cytokine, IL-1 receptor and signalling [33
IL-1RII IL-1 receptor (antagonist) [34
IL-6R IL-6 receptor [63
IL-11R IL-11 receptor [64
CSF-1 A secreted cytokine that influences haematopoietic stem cells to differentiate into macrophages or other related cell types [151
IFNαR2 Subunit of type 1 IFN-α receptor. [96
TNFR1 Pro-inflammatory cytokine, TNF-α receptor. Pro-inflammatory and cell death signalling pathways [52
TREM2 Triggering receptor expressed on myeloid cells 2 (TREM2). Role in chronic inflammations and may stimulate production of constitutive rather than inflammatory chemokines and cytokines [43
CXC16 Transmembrane chemokine. Scavenger receptor on macrophages induces chemotactic response [62
CX3CL1 Transmembrane chemokine [62
CD43 Cell adhesion molecule. Major glycoproteins of thymocytes and T lymphocytes [152
CD44 Cell adhesion molecule. Cell surface glycoprotein and hyaluronan receptor. [153,154
HLA Human leucocyte antigen (HLA). MHC Class I protein [155
HLA-A2 MHC Class I protein. Immune response, T-cell development, synaptic plasticity and refinement [156
SDC1 Herpes simplex receptor. Receptor for HIV-1, Hepatitis E and human papilloma virus [155
SDC2 Herpes simplex receptor [155
SDC3 Herpes simplex receptor. Receptor for HIV-1 and human papilloma virus (HPV) [155,157,158
NOTCH 1–4 Signalling receptors, cell proliferation and differentiation.
Activated by Epstein Barr Virus 
[159161
CD44 Cell adhesion molecule
Entry receptor for Cryptococcus neoformans, lymphocyte activation, recirculation and homing 
[44
CD46 Receptor for adenoviruses, measles virus, human Herpes Virus 6 (HHV-6), Streptococci and Neisseria. Also cleaved by a protease secreted by Porphyromonas gingivalis. Complement and T-cell regulatory functions [162,163
Desmoglein-2 Adenovirus receptor [155,164
LRP1 Lipoprotein receptor 1. Receptor for rhinovirus, Pseudomonas aeruginosa and exotoxin A. [165
LDLR LDL receptor. Receptor for rhinovirus, Hepatitis C and vesicular stomatitis virus [155
VLDLR Very-low-density-lipoprotein receptor (VLDLR). Receptor for rhinovirus [166
ERBB4 Receptor tyrosine kinase. Receptor for vaccinia and other poxviruses [167
NGFR Neurotrophin receptor. Receptor for rabies virus [41,168
Nectin-1α Immunoglobulin superfamily member that mediates cell–cell adhesion. Receptor for herpes simplex virus (HSV) and pseudorabies virus [169
ADAM10 A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10). Cytotoxin Staphylococcus aureus α-haemolysis-mediated cell injury [170,171
Dystroglycan Receptor for the lymphocytic choriomeningitis, Lassa fever viruses and Mycobacterium leprae (the Leprosy pathogen). [155

Consistent with this, in our in vitro and in vivo studies [77], we have shown that loss of PS2 is associated with defective LPS-mediated innate immune responsiveness and that PS2 is a critical determinant of TLR4 signalling. Our observations are consistent with studies reporting that B-cells deficient in both PS1 and PS2 function have a substantial deficit in LPS-induced proliferation and TLR4-mediated signal transduction [76]. However, these findings contrast with another study where it was proposed that PS2 deficiency is associated with increased pro-inflammatory cytokine release in primary murine microglia [78]. These disparate results may be explained by and highlight a cell-specific difference in PS2 functions. In support of this hypothesis, while PS1 and PS2 are expressed throughout most human and mouse tissues [7982], the relative expression levels of Psen1 or Psen2 can differ significantly between tissues and during development [83], suggesting that PS1 and PS2 have different tissue- or development-specific functions. Furthermore, PS1 and PS2 are associated with different knockout phenotypes, with Psen1-deficient mice characterised by embryonic lethality and Psen2-deficient mice being viable and fertile [73,76,8486]; both exhibit distinctions in intracellular localisation and γ-secretase activity [87,88], and each contribute in divergent signalling pathways, for example, PS2 largely affects platelet-derived growth factor signalling [89] and has an important role in facilitating Notch signalling in numerous peripheral organs throughout pharmacological inhibition of PS1 [90]. Collectively, from these reports, the presenilins have indispensable roles in the immune system, reviewed in refs [4,28,91].

γ-Secretase-mediated RIP of immune system ligands, cytokines and antigens

Ectodomain shedding is an established regulatory process associated with both innate and adaptive immunity [89]. Both ADAMs and matrix metalloproteases are involved in aspects of membrane protein ectodomain shedding, immune cell migration, cytokine and chemokine maturation, lymphocyte maturation, clonal expansion, migration and effector function, reviewed in refs [45,89,92]. As outlined earlier, the proteolytic activity of sheddases is often followed by γ-secretase intramembrane proteolysis, and many innate immune receptors and ligands have now been identified as γ-secretase substrates (Table 1), although the direct function of many of their cleavage products remains to be determined. Nonetheless, this is proposed to further enable cells of the immune system to proteolytically regulate cell-type-specific immune activities, reviewed in ref. [93], and emphasise a potentially important role for γ-secretase proteolysis in the pathophysiology of infectious diseases, reviewed in ref. [94]. In addition to cytokine receptors, such as TNFR1 [52], IL-1RI [33,35], IL1-RII [34], IL-6R [63] and IL-11R [64], several additional γ-secretase substrates are also receptors. For example, the type I interferon's (IFNs) bind surface receptors (IFNARs) and induce a signalling cascade via the Janus kinase-signal transducer and activator of the transcription pathway to induce IFN-stimulated gene expression, reviewed in ref. [95]. At least one IFN receptor, IFNAR2, is cleaved by γ-secretase and the ICD was shown to repress gene transcription [96]. TREM2 is also a reported γ-secretase substrate [43]. The interaction of TREM2 and the adapter protein DAP12 activates the pro-inflammatory response of microglia and also regulates other monocytes such as dendritic cells and macrophages [97]. Recent evidence has shown that inhibition of γ-secretase activity affects the TREM2/DAP12 interaction and impacts on microglial phagocytic activity [98]. These findings, supported by previous studies that identify γ-secretase activity in microglial clearance of amyloid-β [99101], suggest a credible role for γ-secretase-mediated proteolysis of TREM2 in AD pathology.

Proteolytic regulation of TNF-α and TNFR1 signalling

Proteolysis is important in the control of TNF-α signalling from the cell surface by the regulation of TNF-α, TNFR1 and TNFR2 ectodomain shedding [9]. TNF-α is first cleaved by TACE/ADAM17 and is then cleaved by the iCliPs, signal peptide peptidase-like 2a (SPPL2a) and 2b (SPPL2b), and both the soluble ectodomain and ICD are biologically active and initiate both extracellular and intracellular signalling events in different cells (Figure 4) [32,48,49]. We have recently added to the regulatory complexity of TNF-α-mediated signalling through the identification of TNFR1 as a novel substrate for the γ-secretase protease [52]. We have shown that following TACE/ADAM17-mediated ectodomain shedding, the remaining membrane-anchored TNFR1 CTF undergoes clathrin-mediated endocytosis and γ-secretase cleavage to generate the TNFR1 ICD. TNFR1 internalisation and the formation of distinct TNFR1 signalling complexes or receptosomes provide the structural basis for spatial compartmentalisation of TNFR1-mediated pro- and anti-apoptotic signalling pathways (Figure 5). A model was initially proposed [102] and subsequently refined wherein TNFR1-mediated signalling arises from two sequential signalling complexes: a plasma membrane-located pro-survival signalling complex I consisting of TNFR1, TNFR-associated death domain (TRADD), receptor-interacting protein kinase-1 (RIPK1), TRAF2 and the cellular inhibitor of apoptosis proteins (cIAPs), which transmit a pro-inflammatory and cell survival signal via the activation of MAPK and NF-κB, and subsequent to TNFR1 internalisation an intracellular pro-apoptotic signalling complex II, which contains TRADD, RIPK1, TRAF2, FAS-associated death domain (FADD) and procaspase-8 [103109]. Inhibition of TNFR1 internalisation also has a role in mediating TNF cytotoxicity and promotion of pro-apoptosis signalling pathways [106,107]. It was shown that inhibition of TNFR1 internalisation prevented the recruitment of the pro-apoptotic proteins FADD and procaspase-8, inhibited the formation of complex II and reduced TNF-induced apoptotic cell death [107]. Consistent with these reports, in our study, we found that deficiency of the presenilins and γ-secretase activity inhibited activation of the JNK MAPK, antagonised JNK-dependent CXCL1 chemokine production, reduced formation of TNFR1 complex II and blocked TNF-stimulated apoptosis [52]. In contrast, loss of γ-secretase activity coincided with increased TNFR1 recruitment of TRAF2, and RIPK1 adaptor proteins and formation of complex I and loss of γ-secretase activity had no measurable effect on TNF-mediated cell surface signalling events, activation of the p38 MAPK and NF-κB signalling pathways and cytokine production. From this and other published works, we propose a model (Figure 5) whereby mechanistically γ-secretase acts as an intracellular regulator of TNFR1-mediated pro-survival and pro-apoptotic signalling pathways [52].

Membrane topologies of γ-secretase and the SPP intramembrane-cleaving aspartyl proteases and their substrates.

Figure 4.
Membrane topologies of γ-secretase and the SPP intramembrane-cleaving aspartyl proteases and their substrates.

Topologies of the γ-secretase protease (left) and of SPPL2a/b, a member of the signal peptide peptidase (SPP/SPPL) family of aspartyl proteases. Note the opposite membrane orientation of TNFR1 a type I (γ-secretase) and TNFα a type II (SPPL2a/b) transmembrane substrates. Arrows indicate the inverted orientations of their respective GxGD and YD active sites and PAL motif.

Figure 4.
Membrane topologies of γ-secretase and the SPP intramembrane-cleaving aspartyl proteases and their substrates.

Topologies of the γ-secretase protease (left) and of SPPL2a/b, a member of the signal peptide peptidase (SPP/SPPL) family of aspartyl proteases. Note the opposite membrane orientation of TNFR1 a type I (γ-secretase) and TNFα a type II (SPPL2a/b) transmembrane substrates. Arrows indicate the inverted orientations of their respective GxGD and YD active sites and PAL motif.

Model of TNFR1 proteolysis and TNF-mediated survival and apoptosis signalling pathways.

Figure 5.
Model of TNFR1 proteolysis and TNF-mediated survival and apoptosis signalling pathways.

TNF-binding and trimerization of TNFR1 enables the recruitment of TRADD, RIPK1, TRAF2 or TRAF5 and the cIAPs, which collectively form a signalling composite called complex I. The resulting K63-linked polyubiquitination of the serine/threonine kinase RIPK1 by the E3 ligases TRAF2 and cIAPs enables an interaction with the IκB kinase complex that mediates the phosphorylation and degradation of IκB inhibitory proteins and activation of the transcription factor NF-κB to promote cell survival and pro-inflammatory signalling pathways. Following RNF8 and E2 ubiquitin-conjugating enzyme ubc13-mediated ubiquitination of TNFR1 and internalisation of TNFR1, TRAF2 promotes K63-linked polyubiquitination of both TNFR1 and PS1. This ubiquitination allows γ-secretase cleavage of TNFR1 and enables interactions between cytosolic TRADD, and FADD enables the recruitment of procaspase-8, establishing pro-apoptotic complex II, and amplification of the apoptotic cascade through activation of caspase-7/caspase-3 and the apoptosome.

Figure 5.
Model of TNFR1 proteolysis and TNF-mediated survival and apoptosis signalling pathways.

TNF-binding and trimerization of TNFR1 enables the recruitment of TRADD, RIPK1, TRAF2 or TRAF5 and the cIAPs, which collectively form a signalling composite called complex I. The resulting K63-linked polyubiquitination of the serine/threonine kinase RIPK1 by the E3 ligases TRAF2 and cIAPs enables an interaction with the IκB kinase complex that mediates the phosphorylation and degradation of IκB inhibitory proteins and activation of the transcription factor NF-κB to promote cell survival and pro-inflammatory signalling pathways. Following RNF8 and E2 ubiquitin-conjugating enzyme ubc13-mediated ubiquitination of TNFR1 and internalisation of TNFR1, TRAF2 promotes K63-linked polyubiquitination of both TNFR1 and PS1. This ubiquitination allows γ-secretase cleavage of TNFR1 and enables interactions between cytosolic TRADD, and FADD enables the recruitment of procaspase-8, establishing pro-apoptotic complex II, and amplification of the apoptotic cascade through activation of caspase-7/caspase-3 and the apoptosome.

RIP of interleukin receptors

While IL-1RI is essential for signal transduction to NF-κB activation following IL-1 binding, IL-1RII is a decoy receptor that binds to excess ligand and does not transmit a signal, as reviewed in ref. [110]. Both of these receptors can be found in a membrane-bound and soluble form, both forms of which are known to have biological functions. It was first reported that IL-1RII was subject to cleavage by α- and β- secretase followed by intramembrane proteolysis by γ-secretase [34], and subsequent work in our laboratory has shown that the type I IL-1R was also subject to cleavage by metalloproteases and γ-secretase [33]. We demonstrated that the IL-1RI ectodomain could be cleaved constitutively and that this cleavage was enhanced by activation of metalloproteases as well as exogenous addition of IL-1 [33]. Ectodomain shedding released a soluble IL-1RI into the extracellular milieu, while the remaining membrane-bound CTD was a substrate for further cleavage by γ-secretase to liberate an IL-1RI ICD into the cytoplasm. Importantly, we demonstrated that inhibition of IL-1RI internalisation inhibits both ectodomain shedding and subsequent γ-secretase cleavage, suggesting that unlike TNFR1, but similar to APP, IL-1RI internalisation is necessary for RIP of IL-1RI (unpublished). In addition to the effects on signalling adaptors and cascades, the γ-secretase cleavage of IL-1RI could directly affect gene expression. As with other γ-secretase substrates, it is feasible that the ICD of IL-1RI could act as a transcription factor. There are nuclear localisation signals within the ICD and IL-1RI has previously been reported to localise to the nucleus [111].

IL-11 is a member of the IL-6 family of cytokines, which signals through a homodimer of the IL-11R and the ubiquitously expressed receptor gp130 [112]. As discussed earlier, both IL-6R and IL-11R are substrates for RIP [63,64]; however, the γ-secretase-generated ICDs derived from both IL-6R and IL-11R are rapidly degraded by the proteasome. Given that no functional role for the γ-secretase-generated ICDs derived from IL-1RI, IL-1RII, IL-6R and IL-11R has been determined, this leads one to speculate that for these interleukin receptors, the γ-secretase cleavage could serve as means to remove unwanted receptor fragments from the plasma membrane, following receptor ectodomain shedding [33,34,63,64]. It thus remains to be determined if the induction of cytokine gene expression following IL-1, IL-6 or IL-11 stimulation is due, in part, to ICD transactivation as well as their respective canonical signal transduction pathways.

γ-Secretase enzyme regulation

With the growing number of newly identified RIP substrates, prominence has now moved onto understanding the regulation of γ-secretase activity and substrate specificity. Not all transmembrane proteins are substrates for RIP, suggesting that the process is controlled, either by the direct regulation of the protease activity or by substrate modifications (localisation or post-translational modifications) that inhibit or enable proteolysis.

Post-translational modification of γ-secretase complex components or their substrates can enable or inhibit substrate recognition and intramembrane proteolysis by the γ-secretase proteases, reviewed in refs [91,113,114]. The role of proteolysis, phosphorylation and ubiquitination in presenilin and γ-secretase activity has been extensively investigated and described in several comprehensive reviews [27,91,113,115,116]. Briefly, it has been demonstrated that PS1 is ubiquitinated by Caenorhabditis elegans SEL-10 [117,118], Fbw7 the mammalian homologue of SEL-10 [119] and by TRAF6, which facilitates Lysine-63 (K63)-linked polyubiquitination of PS1 [120,121]. The ubiquitination of PS1 by C. elegans SEL-10 targets PS1 for degradation through the ubiquitin-proteasome system and antagonises the signalling activity of Notch [117]. Consistent with this, PS1 and Fbw7 interact and regulate the stability and activity of the epidermal growth factor receptor and the NICD [119]. The presenilins contain a conserved TRAF6-binding domain [77] and undergo TRAF6-mediated K63-linked polyubiquitination [120], which increases PS1 holoprotein stability [122]. Furthermore, the interaction between TRAF6 and PS1 has been shown to promote γ-secretase cleavage of p75NTR [122], while the loss of TRAF6 E3 ligase activity reduces γ-secretase cleavage of p75NTR, TGFβ type 1 receptor (TβR1) [123] and IL-1RI [124]. These data suggest that the interaction between TRAF6, PS1 and γ-secretase substrates plays a role in modulating γ-secretase activity. However, given that TRAF6 can ubiquitinate both PS1 and some γ-secretase substrates, the exact role played by TRAF6-mediated ubiquitination of PS1 remains to be fully elucidated. What is clear is that these modifications are not only important for the protease assembly and activity of γ-secretase complexes, but are also essential for the stability and activation of presenilins.

Post-translational modifications can also regulate the proteolysis of substrates. For example, monoubiquitination of Notch is a prerequisite for γ-secretase cleavage [125] and has been proposed as a potential general post-translational mechanism for the regulation of substrate cleavage. Monoubiquitination [126,127] and polyubiquitination [103,128130] have also been reported as important signals for receptor-mediated signalling and internalisation. TRAF6 was initially identified as an adaptor protein that activates NF-κB signalling in IL-1-stimulated cells [42]. TRAF6 is also an ubiquitin E3 ligase that mediates Lys63-linked polyubiquitination of various proteins. The C-terminal TRAF domain mediates protein–protein interactions and the polyubiquitination of various proteins. We reported that both a PS1–TRAF6 interaction and TRAF6-mediated ubiquitination of p75NTR and IL-1RI enhance γ-secretase cleavage of p75NTR and IL-1RI, respectively [35,39]. Others have similarly shown that TRAF6-mediated E3 ligase activity enhances ubiquitination of TβR1 and PS1, leading to enhanced TβR1 ectodomain shedding and generation of an ICD that translocates to the nucleus and binds to the transcriptional co-activator p300, which increases the transcription of several TGFβ target genes, such as Snail1, that encode factors that promote tumour invasiveness [123]. Palmitolyation of juxtamembrane Cys279 has been shown to modulate p75NTR cleavage and downstream signalling [131], suggesting that perhaps both ubiquitination and palmitoylation may function to regulate p75NTR cleavage. Therefore, it is apparent that a multitude of biological events ranging from selective protein–protein interactions to specific post-translational modifications can govern whether a substrate is to be cleaved by γ-secretase.

A growing body of evidence also supports the proposal that the subcellular localisation of γ-secretase substrates is important for intramembrane proteolysis. Post-translational modifications can regulate trafficking of substrates and their γ-secretase-generated cleavage products between distinct subcellular membrane compartments. These modifications have been shown to not only determine subcellular localisation [132] and selectivity of binding-partners [133], but are also important for the assembly and activity of γ-secretase complexes [134]. It has been shown that following cell surface shedding of Notch ectodomain, internalisation of Notch is required for intramembrane proteolysis and generation of NICD [125,135]. Similarly, subsequent to NGF ligand-induced ectodomain shedding, p75NTR C-terminal fragments are localised in early endosomes where they are proposed to undergo proteolysis by γ-secretase [136]. Other examples from our studies include the pro-inflammatory cytokine receptors TNFR1 and IL-1RI [33,52]. In our studies, we have demonstrated that inhibition of dynamin-dependent endocytosis increases cell surface shedding of TNFR1 [52], and antagonises γ-secretase-dependent intramembrane proteolysis of TNFR1 [52], and IL-1RI (unpublished). In the case of APP, inhibition of internalisation was shown to antagonise the generation of soluble sAPPβ (reduce BACE cleavage) and enhance cell surface generation of sAPPα. Of pathological relevance, endocytic disturbance has been described as an early characteristic of Alzheimer's disease pathology, reviewed in ref. [137], and proposed to significantly induce endosomal accumulation of APP and BACE1, which may lead to the exacerbation of Alzheimer's disease pathology [138].

The specificity of γ-secretase complexes is also determined by the compartmentalisation and spatial co-expression of distinct γ-secretase complexes. γ-Secretase activity is observed at the trans-Golgi network, endocytic organelles and plasma membrane, reviewed in ref. [139]. It was recently shown that the N-terminus of PS2 contains a highly conserved unique acidic-dileucine sorting sequence (E16RTSLM21) [26], which fits the acidic-dileucine motif [D/E]xxxL[L/I/M] present in other proteins that are transported to late endosomes/lysosomes [140]. This motif enables PS2 to bind to the γ1–σ1 (AP1G1–AP1S1) hemi-complex of the AP-1 adaptor complex, which enables sorting and localisation of proteins at different stages on the endomembrane system. It was shown that phosphorylation of the E16RTSLM21 motif regulated PS2 interaction with AP-1 and restricted the spatial distribution of PS2 to late endosomal/lysosomal compartments [26]. In contrast, PS1-containing γ-secretase complexes that lack the AP-1 interaction motif are trafficked along a different route, frequenting recycling endosomes, and are more prevalent at the plasma membrane. These observations also support the long-standing proposal that intracellular trafficking and localisation of γ-secretase proteases also regulates the enzyme activities of γ-secretase proteases, reviewed in ref. [25]. PS1-containing γ-secretase complexes are enriched in lipid rafts and their activity is modulated by lipid composition [141145], further implying that the subcellular localisation of γ-secretase is critical to its proteolytic activity. Collectively, these examples highlight the importance of proper spatial distribution and the compartmentalisation requirement of both γ-secretase complexes and substrates for appropriate intramembrane proteolysis, and suggest the existence of similar tissue, cell or subcellular spatial requirements for RIP of other substrates.

The physiological role of the presenilins in signalling pathways downstream from IL-1R and TNFR1 is not yet fully known, but it is feasible that they acts as a scaffold or chaperone for adaptor proteins facilitating the spatial segregation of divergent signalling events arising from each receptor. Several lines of evidence suggest a role for the presenilins in trafficking within the cell and the presenilins are known to localise to the endosome [25,26,146149]. Thus, it is possible that the presenilins help to recruit adaptors to such organelles and this could be critical for signal transduction given the endosomal localisation of certain innate immune receptors, such as the TLRs in the phagosomes of microglia [150].

Conclusion

The discovery that proteases can hydrolyse their substrates within the water-excluding environment of the lipid bilayer has dramatically changed our classical view of proteolytic function. In the past 17 years, significant advances have been made in defining RIP and its physiological significance, yet new insights are constantly expanding how we understanding the multifaceted role of intramembrane proteases. For example, presenilins have many identified γ-secretase-independent functions [91], making their biological significance far more intricate than was previously thought. Therapeutic targeting of RIP in the treatment of immune-related diseases certainly deserves consideration, but should also be addressed with a level of caution. Even considering RIP in the immune system alone, the complexity and diversity of its function is irrefutable. A prime example is the differential roles of Psen2 in controlling inflammation. Immortalised fibroblasts and bone marrow-derived macrophages with Psen2 deficiency exhibit defective LPS-induced immune response and decreased pro-inflammatory cytokine release [77]. In comparison, brain-specific knockout of Psen2 results in increased pro-inflammatory cytokine production in microglia, suggesting that Psen2-mediated γ-secretase activity down-regulates the immune response in the central nervous system [78]. This conflicting function is just one of several examples, which demonstrates the intricacy and variation of RIP in the immune system. Hence, careful consideration must be employed when considering intramembrane proteases as potential therapeutic targets. While significant progress has been made in characterising its function in neurodegeneration, cancer and immunity, substantial research is still necessary to understand its proteolytic mechanism and regulation. In the future, this will aid in the development of novel therapeutics to target RIP in the treatment of a broad range of diseases.

Abbreviations

     
  • Aph-1

    anterior pharynx defective-1

  •  
  • APP

    amyloid-β precursor protein

  •  
  • BACE1 and BACE2

    β-site APP-cleaving enzymes 1 and 2

  •  
  • cIAPs

    cellular inhibitor of apoptosis proteins

  •  
  • CoR

    co-repressors

  •  
  • CREB

    cAMP response element-binding protein

  •  
  • CSL

    CBF 1/Sn(H)/Lag 1

  •  
  • E4ICD

    ErbB4 ICD

  •  
  • EpCAM

    epithelial cell adhesion molecule

  •  
  • EpEx

    EpCAM extracellular domain

  •  
  • EpICD

    EpCAM ICD

  •  
  • FADD

    FAS-associated death domain

  •  
  • FHL2

    four-and-a-half LIM domain protein

  •  
  • ICDs

    intracellular domains

  •  
  • iCliPs

    intramembrane-cleaving proteases

  •  
  • IFN

    interferon

  •  
  • IFNARs

    IFNs bind surface receptors

  •  
  • IL-1

    interleukin-1

  •  
  • IL-11R

    IL-11 receptor

  •  
  • K63

    Lysine-63

  •  
  • LPS

    lipopolysaccharide

  •  
  • MAML

    Mastermind-like proteins

  •  
  • NICD

    Notch ICD

  •  
  • p75NTR

    p75 neurotrophin receptor

  •  
  • Pen-2

    presenilin enhancer-2

  •  
  • PS1

    Presenilin 1

  •  
  • PS2

    Presenilin 2

  •  
  • RIP

    regulated intramembrane proteolysis

  •  
  • RIPK1

    receptor-interacting protein kinase-1

  •  
  • TACE

    TNF-α-converting enzyme

  •  
  • TLR

    Toll-like receptor

  •  
  • TNFR1

    tumour necrosis factor receptor, type 1

  •  
  • TNF-α

    tumour necrosis factor-α

  •  
  • TRADD

    TNFR-associated death domain

  •  
  • TRAF

    tumour necrosis factor receptor-associated factor

  •  
  • TRAF2

    tumour necrosis factor receptor-associated factor-2

  •  
  • TRAF6

    TNFR-associated factor 6

  •  
  • TREM2

    triggering receptor expressed on myeloid cells-2

  •  
  • TβR1

    TGFβ type 1 receptor

Funding

This work was supported and funded by grants from Science Foundation Ireland [02/IN1/B218 and 09/IN.1/B2624] and a student bursary to C.C.-V. from the College of Science Engineering & Food Science, University College Cork.

Acknowledgments

We apologise to all colleagues whose work has not been discussed or cited owing to space limitations.

Competing Interests

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

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