Autophagy is conventionally described as a degradative, catabolic pathway and a tributary to the lysosomal system where the cytoplasmic material sequestered by autophagosomes gets degraded. However, autophagosomes or autophagosome-related organelles do not always follow this route. It has recently come to light that autophagy can terminate in cytosolic protein secretion or release of sequestered material from the cells, rather than in their degradation. In this review, we address this relatively new but growing aspect of autophagy as a complex pathway, which is far more versatile than originally anticipated.

Introduction

The standard mode of secretion for proteins is the conventional secretory pathway. These proteins possess at their N-terminus a leader peptide (or signal peptide), which allows them to cotranslationally enter the lumen of the ER and then move on to the Golgi apparatus to be secreted by exocytosis of post-Golgi carriers [1]. However, leaderless cytosolic proteins, which do not enter the ER-Golgi secretory pathway, can be actively secreted (reviewed in ref. [2]) or passively released from cells (cell lysis). A classic example of an unconventionally secreted protein is the proinflammatory cytokine interleukin (IL)-1β, first reported in 1990 as being secreted from mammalian cells despite the absence of a leader peptide [3,4]. In this review, we summarize evidence for autophagy as a mechanism for unconventional secretion of such leaderless cargo.

There are several types of degradative processes (macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA)) that involve lysosomes and are often classified under the collective term “autophagy”. Here, we use the term autophagy only in reference to macroautophagy. The principal morphological feature of this form of autophagy is the formation of a double-membrane organelle, called the autophagosome, which encloses cytosolic cargo and typically delivers it to lysosomes for degradation (reviewed in ref. [5]). Autophagy is induced by various stimuli (reviewed in ref. [6]), classically by starvation and can be bulk or selective (reviewed in ref. [7]). There are three branches of autophagy (Figure 1), depending on the final functional outcome. The first branch is “metabolic autophagy”, when autophagy degrades and recycles large polymeric constituents of the cytosol into nutrients to maintain cellular homeostasis at times of amino acid and energy shortage or absence of growth factors (reviewed in ref. [8]). The second branch is “quality control autophagy”, which is non-nutritional, when autophagy selectively removes damaged organelles, protein aggregates or invading microbes by delivering them to lysosomes for degradation/elimination (reviewed in refs. [7,9]). The third, less appreciated but growing in scope branch of autophagy is “secretory autophagy” (reviewed in ref. [10]). During secretory autophagy, cytoplasmic cargo is sequestered and secreted from the cell for the purpose of extracellular signaling (as in the case of IL-1β) or as an alternative mode of elimination of intracellular debris.

Secretory autophagy facilitates release of a range of cytosolic cargo in mammalian cells

Figure 1
Secretory autophagy facilitates release of a range of cytosolic cargo in mammalian cells

The three outcomes of autophagy. (1) Metabolic autophagy recycles nutrients by degrading cytosolic proteins to maintain metabolic homeostasis. (2) Quality control autophagy eliminates protein aggregates, damaged or surplus organelles, and invading microbes. (3) Secretory autophagy is a form of unconventional secretion enabling cells to secrete cytosolic proteins with extracellular functions. Beyond this, secretory autophagy has been implicated in extracellular release of aggregate-forming proteins, microbes and organellar material, such as mitochondria.

Figure 1
Secretory autophagy facilitates release of a range of cytosolic cargo in mammalian cells

The three outcomes of autophagy. (1) Metabolic autophagy recycles nutrients by degrading cytosolic proteins to maintain metabolic homeostasis. (2) Quality control autophagy eliminates protein aggregates, damaged or surplus organelles, and invading microbes. (3) Secretory autophagy is a form of unconventional secretion enabling cells to secrete cytosolic proteins with extracellular functions. Beyond this, secretory autophagy has been implicated in extracellular release of aggregate-forming proteins, microbes and organellar material, such as mitochondria.

Autophagy is regulated through all of its steps by more than 30 autophagy-related (ATG) proteins. In brief, the ULK and BECLIN1 complexes regulate canonical autophagy induction upon stress conditions. The ATG12–ATG5–ATG16L1 complex promotes the lipidation of the ATG8 family members (e.g. LC3) to produce a closed double-membrane autophagosome which, when autophagosomes enter the conventional degradative pathway (Figure 1), is able to fuse with lysosomes leading to degradation of the captured contents (reviewed in [5]). However, recent studies (Table 1) have shown that the process of autophagy can terminate differently, in secretion rather than degradation in autolysosomes. Indeed, autophagy is involved in secretion of the highly conserved AcetylCoA binding protein (Acb1/AcbA) [20, 28], IL-1β [19,26,50] and possibly in the external release of a range of cytosolic proteins and other cytoplasmic constituents [1119,2125,27,2948,64]. In this review, we will focus on diverse cargo that can be secreted/released extracellularly by autophagy-related processes and elaborate on the different mechanisms that enable secretory autophagy.

Molecular mechanism of secretory autophagy

Autophagy was first implicated in the unconventional secretion of the cytosolic Acetyl CoA binding proteins Acb1 in yeast and AcbA in the slime mold Dictyostelium [20,28]. Sporulation in Dictyostelium is controlled by autophagy-inducing conditions and depends on AcbA secretion [28]. Since Acetyl CoA plays an important role in metabolism and control of autophagy in mammalian cells [51], unconventional secretion of Acb1 and AcbA via autophagy in lower eukaryotes as well as the possible secretion of Acb1’s evolutionarily conserved mammalian ortholog diazepam binding inhibitor (DBI) may provide an interesting regulatory loop. Secretion of Acb1 depends on ATG genes controlling autophagosome formation (notably Atg5, Atg8, and Atg12), a Golgi reassembly stacking protein (GRASP in mammals/Grh1 in yeast; known for its conserved role in unconventional secretion) and Ypt6, a Rab GTPase involved in recycling of endosomal compartments [20,28]. Equally interesting and physiologically highly significant is the unconventional secretion of the marquee proinflammatory cytokine IL-1β, which has been shown to depend on autophagy [19]. In mammalian cells, comparatively to Acb1, secretory autophagy of IL-1β also depends upon the autophagy factor ATG5, a GRASP homolog (GRASP55, also affecting general autophagy in mammalian cells), and a small GTPase, RAB8A, which regulates vectorial sorting to the plasma membrane [19].

Secretory autophagy of IL-1β

Several studies have indicated participation of the autophagy molecular apparatus in IL-1β secretion and explored its mechanisms [19,26,49]. Zhang et al. [49] reconstituted an autophagy-regulated secretion of mature IL-1β (mIL-1β) in a nonmacrophage cell line, showing that cytoplasmic mIL-1β enters into the lumen of a vesicular intermediate, which later may turn into an autophagosome and fuse one way or another with the plasma membrane. The protein unfolding and translocation of mIL-1β across the membrane depend on two KFERQ-like motifs (not to be confused with the CMA signals), essential for the association of mIL-1β with HSP90 as a helper in this process. In this case, the location of mIL-1β may not be in the autophagosomal lumen but between the outer and the inner membrane after the formation of the autophagosome double membrane. The authors of that study also confirmed that IL-1β secretion requires GRASPs, and showed that multivesicular body (MVB) formation helps in the process [49]. The above study suggests one mechanism for how IL-1β is recognized for delivery to autophagic organelles and how it is protected from degradation in the lumen of autophagosomes (since it appears not to enter it) and thus is preserved for secretion.

Recently, a different study has identified the first specific receptor for secretory autophagy and defined the SNARE apparatus that bypasses autophagosomal maturation but instead leads to secretion of the cargo at the plasma membrane [26,50]. This newly idenitfied secretory autophagy receptor, TRIM16 (previously known as estrogen-responsive B box protein EBBP) [52], serves as a cargo receptor for secretory autophagy and regulates autophagy-dependent unconventional secretion of IL-1β in response to lysosomal damage. Galectin-8, which belongs to a family of lectin proteins that recognize damaged endomembranes, is also a contributor to the secretion of IL-1β upon lysosomal damage, a condition that often leads to inflammasome activation, a process that serves as a prelude to IL-1β activation and secretion. TRIM16 is in a complex with SEC22b, an R-SNARE protein better known for its role in ER-to-Golgi trafficking, but not syntaxin 17 (STX17) a Qa-SNARE protein implicated in fusion between autophagosomes and lysosomes, suggesting that IL-1β-containing autophagic vesicles do not fuse with lysosomes for secretion. Instead, plasma membrane Qa-SNARE protein STX3 (or alternatively STX4) and a Qbc SNARE (SNAP23 or SNAP29) contribute the remaining three SNARE domains for completion of the 4-helix bundle and secretion of IL-1β. Importantly, this secretory autophagy pathway may also be involved in secretion of other leaderless cytosolic proteins, such as ferritin [26] (Figure 2A).

Mechanisms and membranous organelles contributing to secretory autophagy

Figure 2
Mechanisms and membranous organelles contributing to secretory autophagy

(A) Autophagy induction by starvation or lysosomal damage induces the maturation of pro-IL-1β (pro-IL1B) into mIL-1β (mIL1B). Next, mIL-1β is recognized by HSP90, LGALS8 (galectin-8), and TRIM16, promoting its sequestration in LC3+SEC22B+STX17 autophagic vacuoles; ATG5, ATG16L1, and GRASP55 all contribute. mIL-1β is sequestered either within the lumen of autophagosomes but can also translocate into the intermembrane space between the two aspects of the double membranes typical of autophagosomes. Then, fusion with plasma membrane is mediated by the SNARE complex STX3 or 4, SEC22B and SNAP23 or 29, leading to secretion of mIL-1β from the cells. (B) IFN-γ promotes the fusion of ANXA2-containing autophagosomes with MVBs via RAB11. Dependent on RAB8A and RAB27A, the amphisome formed fuses with the plasma membrane to secrete ANXA2-positive exosomes. Autophagy induction by starvation, rapamycin, or IFN-I competes with this secretory process, favoring instead fusion of autophagosomes, MVBs and amphisomes with lysosomes resulting in degradation of its content. This inhibits exosome secretion. (C) The accumulation of Aβ peptide induces the enclosure of insulin-degrading enzyme (IDE) into autophagosomes, which then fuse with lysosomes. The autolysosome formed fuses with plasma membrane dependent on RAB8A to induce the secretion of IDE, protected from degradation by its SlyX motif. (D) Paneth cells invaded by invasive bacteria such as Salmonella typhimurium undergo ER stress, which induces the incorporation of lysozyme into LC3-positive vesicles, dependent on the PERK–eIF2α pathway and ATG16L1. These vesicles then fuse with plasma membrane to secrete lysozyme via a RAB8A-dependent exocytosis.

Figure 2
Mechanisms and membranous organelles contributing to secretory autophagy

(A) Autophagy induction by starvation or lysosomal damage induces the maturation of pro-IL-1β (pro-IL1B) into mIL-1β (mIL1B). Next, mIL-1β is recognized by HSP90, LGALS8 (galectin-8), and TRIM16, promoting its sequestration in LC3+SEC22B+STX17 autophagic vacuoles; ATG5, ATG16L1, and GRASP55 all contribute. mIL-1β is sequestered either within the lumen of autophagosomes but can also translocate into the intermembrane space between the two aspects of the double membranes typical of autophagosomes. Then, fusion with plasma membrane is mediated by the SNARE complex STX3 or 4, SEC22B and SNAP23 or 29, leading to secretion of mIL-1β from the cells. (B) IFN-γ promotes the fusion of ANXA2-containing autophagosomes with MVBs via RAB11. Dependent on RAB8A and RAB27A, the amphisome formed fuses with the plasma membrane to secrete ANXA2-positive exosomes. Autophagy induction by starvation, rapamycin, or IFN-I competes with this secretory process, favoring instead fusion of autophagosomes, MVBs and amphisomes with lysosomes resulting in degradation of its content. This inhibits exosome secretion. (C) The accumulation of Aβ peptide induces the enclosure of insulin-degrading enzyme (IDE) into autophagosomes, which then fuse with lysosomes. The autolysosome formed fuses with plasma membrane dependent on RAB8A to induce the secretion of IDE, protected from degradation by its SlyX motif. (D) Paneth cells invaded by invasive bacteria such as Salmonella typhimurium undergo ER stress, which induces the incorporation of lysozyme into LC3-positive vesicles, dependent on the PERK–eIF2α pathway and ATG16L1. These vesicles then fuse with plasma membrane to secrete lysozyme via a RAB8A-dependent exocytosis.

Secretory autophagy via MVBs

MVBs are a type of late endosome-containing intralumenal vesicles (ILVs) formed by the invagination of the endosomal membrane into the luminal space. They can mature to induce the degradation of their contents but can also fuse with the plasma membrane to release their ILVs (a subset known as exosomes) and cargo from the cells. Moreover, it has been known for two decades that MVBs can also fuse with autophagosomes to form amphisomes that will fuse with lysosomes [53].

Recently, MVBs have been implicated in the autophagy secretion of Annexin A2 (ANXA2), a phospholipid-binding protein in human lung epithelial cells activated by IFN-γ [15]. Indeed, the authors showed that IFN-γ induced the colocalization of ANXA2 with LC3-positive profiles and CD63, a MVB marker. In this process, the fusion between ANXA2-positive autophagosomes and MVBs is mediated by RAB11. The ANXA2-containing amphisomes do not fuse with lysosomes but rather with plasma membrane via RAB8A, which controls the autophagy-dependent secretion of IL-1β [19] and RAB27A, known for its role in the transport of MVBs to the plasma membrane [54] (Figure 2B).

Other reports have shown, however, that autophagy induced by starvation, rapamycin [55] or type I interferon (IFN-I) [56] could lead to an inhibition of exosome secretion by promoting the fusion of MVBs with lysosomes. This variance relative to IFN-γ-induced autophagy secretion via MVBs could be partly explained by the fact that IFN-I responses are generally associated with viral infection and inhibition of secretion could lead to a reduction in viral propagation. Indeed, hepatitis B virus (HBV) has been observed to adjust its own secretion by promoting the fusion of autophagosomes and MVBs with lysosomes, via an increase in RAB7 activity [57]. This could allow the HBV virus to reduce the immune response against it (Figure 2B).

Secretory autophagy dependent on lysosomes

In 2014, a study revealed an autophagy-dependent secretion of ATP via the process of lysosomal exocytosis [29]. Indeed, in a model of immunogenic cell death of cancer cells, lysosomes fuse with plasma membrane to allow release of ATP, using a process that could be completed only in autophagy-competent cells, able to maintain a lysosomal pool of ATP.

Recently, this process has been also proven to work for proteins, as described for the insulin-degrading enzyme (IDE) [42], a cytosolic leaderless protease that cleaves amyloid β (Aβ) peptide in the extracellular space, which otherwise accumulates in abnormal plaques in Alzheimer’s disease. Indeed, the authors have shown [42] that Aβ-promotes IDE secretion from astrocytes via its packaging in LC3-positive structures that become positive for lysotracker staining, an acidic vesicle tracer, and RAB8A, which is known to control the autophagy-dependent secretion of IL-1β [19]. In this case, the SlyX motif in the IDE protein confers its protection from lysosomal degradation and permits its secretion instead (Figure 2C).

Secretory autophagy: more than one way to achieve a common goal

For the purpose of making a distinction of how autophagy influences secretion, which encompasses unconventional and conventional pathways, we will compare and contrast IL-18 and lysozyme as two completely different secretory autophagy cargos. Like IL-1β, IL-18 is a leaderless cytosolic protein (Figure 1 and Table 1A). In contrast, lysozyme contains a signal peptide and enters the regulated branch of the conventional secretory pathway from ER to Golgi and then to granules where it is stored for secretion when necessary (reviewed in refs [58,59]). IL-18 is exported at least in part by secretory autophagy similarly to IL-1β, as its secretion is notably dependent on autophagy induction conditions and GRASP55 [19]. The unconventional secretion of cytosolic proteins such as IL-18 should not be confused with conventional secretion of proteins stored in intracellular granules, such as lysozyme. However, the complexity and further elegance of secretory autophagy, emerges when autophagy assumes the role of a salvage pathway in cells infected with invasive bacteria that disrupt conventional secretion; in this case, autophagic organelles come to the rescue and salvage the secretion of lysozyme through secretory autophagy [12] (Table 1B). It has been recently shown in a set of elegant experiments that Paneth cells can maintain lysozyme secretion during peak demand when disrupted by pathogens, thanks to secretory autophagy [12]. During bacterial infection, ER stress is induced in Paneth cells through the PERK–eIF2α pathway. This leads to a selective packaging of lysozyme (but not of the α-defensin Cryptdn 5) in large LC3-positive vesicles marked with RAB8A (which, of note, also plays a role in secretory autophagy of IL-1β [19]) and are directed to the apical cell surface to secrete lysozyme (Figure 2D). This pathway is insensitive to brefeldin A, which blocks the conventional secretory pathway via ER and Golgi, indicating that this route for lysozyme secretion can bypass the ER–Golgi pathway [12]. The lysozyme secretion via autophagy is clearly dependent on ER stress because this pathway is sensitive to the inhibitor of ER stress, tauroursodeoxycholic acid, providing a chemical antagonist that may be useful in future studies [12].

Table 1
Secretory autophagy and related processes v2.0*
Cargo Methods Effects Function References 
A. Autophagy secretion of leaderless cytosolic proteins with extracellular functions 
Acb1 Analysis of yeasts lacking Atg genes; induction of autophagy by starvation but not with rapamycin Autophagy induction enhanced and Atg factors required for Acb1 secretion Necessary for yeast sporulation; in mammals, precursor to neuropeptides and role in metabolism [20,28
IL-1β Pharmacological and starvation modulation of autophagy; knockdowns and knockouts of ATG factors and RAB8 Autophagy enhanced IL-1β secretion Key proinflammatory cytokine processed by inflammasome [19,27,34,37,48
TFEB and TFE3 double knockout Autophagy is required for IL-1β secretion [36
IL-18 Pharmacological and physiological modulation of autophagy Autophagy enhanced IL-18 secretion Inflammasome-processed cytokine with roles in cell-mediated immunity and retinal health [19
HMGB1 Atg5 knockout; physiological modulation of autophagy without causing lysis Autophagy enhanced and Atg5 were necessary for secretion of HMGB1 Damage-associated molecular pattern— inflammatory mediator [19,45
Galectin-3 Beclin 1 knockdown in β-glucan-stimulated cells via Dectin 1 Beclin 1 was necessary for secretion A cytosolic β-galactoside-binding protein with roles in autophagy, cancer, heart disease, and stroke [34
Annexin I, tubulin As above As above Proposed members of Dectin-induced secretome [34
B. Autophagy assisting conventional secretion 
Lysozyme Atg16L1 mutation (T300A); pharmacological modulation of autophagy in microbe-infected Paneth cells Autophagy is necessary for lysozyme secretion Rescue of lysozyme secretion when conventional secretion is impaired by pathogenic microbes [12
IL-2 TFEB and TFE3 double knockout Autophagy is required for IL-2, -27, and CSF2 secretion Key mediators of the inflammatory response [36
IL-27 
CSF2 
CFS1 TFEB and TFE3 double knockout Autophagy is required for CFS1 secretion Mediator of macrophage differentiation [36
CCL2 TFEB and TFE3 double knockout Autophagy is required for CCL2 secretion Mediator of macrophage infiltration and migration to sites of inflammation [36
C. Aggregate extrusion by secretory autophagy 
α-Synuclein Inhibition of degradative autophagic flux; knockdown of Atg5; analysis of HDAC6 and Rab8 Inhibition of autophagic maturation enhanced α-synuclein release Interneuronal transmission of α-synuclein species (modified or aggregated) in Parkinson’s disease [21
Amyloid β (Aβ) Analysis of neuron-specific Atg7-deficient APP transgenic mice and pharmacological stimulation of autophagy Increased intracellular Aβ accumulation Alzheimer’s disease pathology and memory impairment [32
D. Secretion or release of a range of cargo—from small molecules to parts of or whole organelles 
ATP-containing lysosomes Atg5 knockdown after induction of immunologic cell death Autophagy allows ATP release ATP is one of the three major agonists stimulating a tumor-specific immune response [29
ANXA2-containing exosomes ATG5, RAB8A, RAB11, and RAB27A knockdown; pharmacological modulation of autophagy in IFN-γ-stimulated cells Autophagosomes containing ANXA2 fuse with MVBs to form amphisomes, which will allow the secretion of ANXA2 -exosomes; dependent on RAB8A, RAB27a, and RAB11 ANXA2 enhances efferocytosis [15
Insulin-degrading enzyme (IDE) Atg5 knockdown; inhibition of degradative autophagic flux Autophagy allows IDE secretion; dependent on lysosomal function, Rab8, and GORASP IDE reduced secretion could be associated to Alzheimer’s disease [42
Mitochondria Induction of autophagy; autophagic receptor NIX dependent clearance; ultrastructural analyses Mitochondria removal from developing reticulocytes; release of mitochondrial components Developmentally regulated clearance of mitochondria [35,39
Induction of autophagy by LPS; ATG5 knockout; pharmacological modulation of autophagy Mitochondria release could activate immune cells; dependent on Atg5 and lysosomal function May be involved in the pathogenesis of sepsis/endotoxemia [46
Mixed organellar remnants Detection of autophagic markers Release of an LC3+ compartment with organellar remnants (ER, Golgi, plasma membrane) Final stages of reticulocyte development [24
Autophagic organelles Physiological and pharmacological modulation of autophagy Extracellular export of autophagic vacuoles without cell membrane permeabilization Linking secretory autophagy with caspase activation [41
Phagolysosomes Purinergic stimulation and microtubule perturbation Release of microbial material captured in autophagolysosomes Possible immune adjuvant or alternative elimination mechanism [44
E. Secretory autophagy as a process spreading intracellular microbes 
Mycobacterium marinum Genetic and cell biological analyses in the ameba Dictyostelium as an infected host Atg1-, Atg6 (Beclin)-, Atg7- dependent, but independent on SQSTM1 (p62 ortholog) Intercellular spread of infection [22
Brucella abortus Genetic and cell biological analyses ULK1-, Beclin 1-, ATG14L-, and PI3-kinase dependent (but independent on ATG5, ATG16L1, ATG4B, ATG7, and LC3B) Intercellular spread of infection [43
Epstein–Barr virus (EBV) Atg5, Beclin1, Atg16L1, Atg12 knockdown; pharmacological modulation of autophagy Autophagy promotes viral production; dependent on Atg5, Beclin1, Atg16L1, and Atg12; EBV particles contain LC3 Spread of infection [23,33
Poliovirus Enteroviruses Genetic and pharmacological manipulation of autophagy and time lapse microscopy Virus released nonlytically within phosphatidylserine-rich vesicles of autophagic origin that are formed within lysosomal enzymes-negative syntaxin 17-negative, LC3, and Beclin 1-dependent compartments Intercellular spread of infection [16,25,64
Hepatitis C virus (HCV) ATG7, Beclin1, Rubicon, Vps34, DFCP1 knockdown Autophagy promotes exosomal release of HCV; dependent on ATG7, Beclin1, RAB27A, Rubicon, Vps34 and DFCP1 Spread of infection [31,40,47
Morbillivirus Atg7 knockdown, chloroquine Virus spread associated with syncytia formation Spread of infection [18
Coxsackievirus Analysis of extracellular microvesicles containing viruses Released virus detected in LC3II+ extracellular microvesicles Intercellular spread of infection [38
Infleunza A virus Viral M2 protein association with LC3 Plasma membrane translocation of LC3 Supporting alternative (filamentous) mode of budding [11
Varicella Zoster virus (VZV) Atg5 knockdown; pharmacological modulation of autophagy Autophagy involved in VZV production; dependent on Atg5; VZV colocalize with LC3B and RAB11 Spread of infection [13,14
F. Secretory autophagy as a process expelling intracellular microbes 
Uropathogenic Escherichia coli (UPEC) ATG5 and Beclin1 knockdown; overexpression of ATG4 dominant negative mutant; Atg3 knockout; bladder epithelial cells (BECs) as an infected host Autophagy promotes bacterial expulsion of UPECs sequestered in neutral lysosomes; dependent on ATG5, VAMP3, RAB7, SYT7, and TRPML3 Autonomous cell defense against UPEC [30
Cargo Methods Effects Function References 
A. Autophagy secretion of leaderless cytosolic proteins with extracellular functions 
Acb1 Analysis of yeasts lacking Atg genes; induction of autophagy by starvation but not with rapamycin Autophagy induction enhanced and Atg factors required for Acb1 secretion Necessary for yeast sporulation; in mammals, precursor to neuropeptides and role in metabolism [20,28
IL-1β Pharmacological and starvation modulation of autophagy; knockdowns and knockouts of ATG factors and RAB8 Autophagy enhanced IL-1β secretion Key proinflammatory cytokine processed by inflammasome [19,27,34,37,48
TFEB and TFE3 double knockout Autophagy is required for IL-1β secretion [36
IL-18 Pharmacological and physiological modulation of autophagy Autophagy enhanced IL-18 secretion Inflammasome-processed cytokine with roles in cell-mediated immunity and retinal health [19
HMGB1 Atg5 knockout; physiological modulation of autophagy without causing lysis Autophagy enhanced and Atg5 were necessary for secretion of HMGB1 Damage-associated molecular pattern— inflammatory mediator [19,45
Galectin-3 Beclin 1 knockdown in β-glucan-stimulated cells via Dectin 1 Beclin 1 was necessary for secretion A cytosolic β-galactoside-binding protein with roles in autophagy, cancer, heart disease, and stroke [34
Annexin I, tubulin As above As above Proposed members of Dectin-induced secretome [34
B. Autophagy assisting conventional secretion 
Lysozyme Atg16L1 mutation (T300A); pharmacological modulation of autophagy in microbe-infected Paneth cells Autophagy is necessary for lysozyme secretion Rescue of lysozyme secretion when conventional secretion is impaired by pathogenic microbes [12
IL-2 TFEB and TFE3 double knockout Autophagy is required for IL-2, -27, and CSF2 secretion Key mediators of the inflammatory response [36
IL-27 
CSF2 
CFS1 TFEB and TFE3 double knockout Autophagy is required for CFS1 secretion Mediator of macrophage differentiation [36
CCL2 TFEB and TFE3 double knockout Autophagy is required for CCL2 secretion Mediator of macrophage infiltration and migration to sites of inflammation [36
C. Aggregate extrusion by secretory autophagy 
α-Synuclein Inhibition of degradative autophagic flux; knockdown of Atg5; analysis of HDAC6 and Rab8 Inhibition of autophagic maturation enhanced α-synuclein release Interneuronal transmission of α-synuclein species (modified or aggregated) in Parkinson’s disease [21
Amyloid β (Aβ) Analysis of neuron-specific Atg7-deficient APP transgenic mice and pharmacological stimulation of autophagy Increased intracellular Aβ accumulation Alzheimer’s disease pathology and memory impairment [32
D. Secretion or release of a range of cargo—from small molecules to parts of or whole organelles 
ATP-containing lysosomes Atg5 knockdown after induction of immunologic cell death Autophagy allows ATP release ATP is one of the three major agonists stimulating a tumor-specific immune response [29
ANXA2-containing exosomes ATG5, RAB8A, RAB11, and RAB27A knockdown; pharmacological modulation of autophagy in IFN-γ-stimulated cells Autophagosomes containing ANXA2 fuse with MVBs to form amphisomes, which will allow the secretion of ANXA2 -exosomes; dependent on RAB8A, RAB27a, and RAB11 ANXA2 enhances efferocytosis [15
Insulin-degrading enzyme (IDE) Atg5 knockdown; inhibition of degradative autophagic flux Autophagy allows IDE secretion; dependent on lysosomal function, Rab8, and GORASP IDE reduced secretion could be associated to Alzheimer’s disease [42
Mitochondria Induction of autophagy; autophagic receptor NIX dependent clearance; ultrastructural analyses Mitochondria removal from developing reticulocytes; release of mitochondrial components Developmentally regulated clearance of mitochondria [35,39
Induction of autophagy by LPS; ATG5 knockout; pharmacological modulation of autophagy Mitochondria release could activate immune cells; dependent on Atg5 and lysosomal function May be involved in the pathogenesis of sepsis/endotoxemia [46
Mixed organellar remnants Detection of autophagic markers Release of an LC3+ compartment with organellar remnants (ER, Golgi, plasma membrane) Final stages of reticulocyte development [24
Autophagic organelles Physiological and pharmacological modulation of autophagy Extracellular export of autophagic vacuoles without cell membrane permeabilization Linking secretory autophagy with caspase activation [41
Phagolysosomes Purinergic stimulation and microtubule perturbation Release of microbial material captured in autophagolysosomes Possible immune adjuvant or alternative elimination mechanism [44
E. Secretory autophagy as a process spreading intracellular microbes 
Mycobacterium marinum Genetic and cell biological analyses in the ameba Dictyostelium as an infected host Atg1-, Atg6 (Beclin)-, Atg7- dependent, but independent on SQSTM1 (p62 ortholog) Intercellular spread of infection [22
Brucella abortus Genetic and cell biological analyses ULK1-, Beclin 1-, ATG14L-, and PI3-kinase dependent (but independent on ATG5, ATG16L1, ATG4B, ATG7, and LC3B) Intercellular spread of infection [43
Epstein–Barr virus (EBV) Atg5, Beclin1, Atg16L1, Atg12 knockdown; pharmacological modulation of autophagy Autophagy promotes viral production; dependent on Atg5, Beclin1, Atg16L1, and Atg12; EBV particles contain LC3 Spread of infection [23,33
Poliovirus Enteroviruses Genetic and pharmacological manipulation of autophagy and time lapse microscopy Virus released nonlytically within phosphatidylserine-rich vesicles of autophagic origin that are formed within lysosomal enzymes-negative syntaxin 17-negative, LC3, and Beclin 1-dependent compartments Intercellular spread of infection [16,25,64
Hepatitis C virus (HCV) ATG7, Beclin1, Rubicon, Vps34, DFCP1 knockdown Autophagy promotes exosomal release of HCV; dependent on ATG7, Beclin1, RAB27A, Rubicon, Vps34 and DFCP1 Spread of infection [31,40,47
Morbillivirus Atg7 knockdown, chloroquine Virus spread associated with syncytia formation Spread of infection [18
Coxsackievirus Analysis of extracellular microvesicles containing viruses Released virus detected in LC3II+ extracellular microvesicles Intercellular spread of infection [38
Infleunza A virus Viral M2 protein association with LC3 Plasma membrane translocation of LC3 Supporting alternative (filamentous) mode of budding [11
Varicella Zoster virus (VZV) Atg5 knockdown; pharmacological modulation of autophagy Autophagy involved in VZV production; dependent on Atg5; VZV colocalize with LC3B and RAB11 Spread of infection [13,14
F. Secretory autophagy as a process expelling intracellular microbes 
Uropathogenic Escherichia coli (UPEC) ATG5 and Beclin1 knockdown; overexpression of ATG4 dominant negative mutant; Atg3 knockout; bladder epithelial cells (BECs) as an infected host Autophagy promotes bacterial expulsion of UPECs sequestered in neutral lysosomes; dependent on ATG5, VAMP3, RAB7, SYT7, and TRPML3 Autonomous cell defense against UPEC [30
*

Modified and updated from Ponpuak et al. [10].

Aggregate removal by secretory autophagy

The accumulation of protein aggregates in cells has been linked to several pathologies such as Parkinson’s and Alzheimer’s diseases with the accumulation of α-synuclein and Aβ peptide respectively. Autophagy has been described as a process to export these aggregates (Figure 1 and Table 1C) to protect cells against their intracellular accumulation. Again, the process implicated in that type of secretory autophagy is relatively comparable to IL-1β secretion. Indeed, α-synuclein aggregates are found in autophagosomes (dependent on Atg5), which do not fuse with lysosomes but are delivered to plasma membrane via a Rab GTPase, Rab27A [21].

Secretory autophagy of organelles and vesicles

Autophagy allows for the formation of a double-membrane organelle, which engulfs cytoplasmic material, including organelles such as damaged lysosomes, surplus or damaged peroxisomes, fragments of the nucleus or the mitochondria, to allow their degradation (reviewed in [60]). However, in some circumstances, these organelles can be secreted by an autophagy-associated mechanism (Figure 1 and Table 1D). Indeed, mitochondrial material is released by LPS-induced autophagy in mouse embryonic fibroblasts (MEFs), and this process is inhibited upon Atg5 knockout (KO) [46]. This process is dependent on lysosomal function but further studies are needed to better understand the mechanisms involved. On the other hand, as mentioned before, autophagy has also been implicated in the secretion of cargo enclosed in a single membrane vesicle named exosome, originating from an amphisome. As phagocytosis of exosomes has been already implicated in immune responses (reviewed in ref. [61]), the autophagy-dependent secretion of exosomes could be of particular interest to study in this and other contexts.

Secretory autophagy as a process expelling but also spreading intracellular microbes

Numerous studies have shown that intracellular pathogens, such as bacteria and viruses, can manipulate autophagy to avoid clearance and promote their growth (reviewed in refs [62] and [63]). Moreover, autophagy is also employed by these pathogens to promote their exit into the extracellular media and the infection of neighboring cells (Figure 1 and Table 1E). For example, Hepatitis C Virus (HCV) uses the autophagy machinery to promote HCV release in the extracellular space via exosomes [40]. Likewise, mammalian cells have also developed an autophagy-based process to induce the expulsion of pathogens from their interiors (Table 1F). Indeed, a recent publication has shown that autophagy targets uropthogenic E. coli (UPEC) upon infection of bladder epithelial cells [30]. However, UPECs developed a mechanism to inhibit their autophagy-dependent degradation by neutralizing lysosomal pH. This is detected by mucolipin TRP channel 3 (TRPML3), a transient receptor potential cation channel localized to lysosomes. This leads to a fusion of UPEC-containing autophagosomes with MVBs, which then target their contents into lysosomes. Subsequently, the UPEC-containing exosomes are released from cells [30]. In that case, the release of UPECs shielded in exosomes could be of particular interest for induction of an immunological response after their phagocytosis by dendritic cells. This may also reduce the risk of spreading of infection.

Concluding remarks

In this review, we have summarized evidence that mammalian cells have evolved several ways to secrete or extrude cytosolic constituents by autophagy-dependent processes. The wide assortment of these varied processes also reflect a broad range of functionalities including signaling, as in the case of IL-1β, or at the other end of the spectrum, reflect an alternative way to get rid of the intracellular debris when the degradative capacity of cellular lysosomes is overwhelmed. This could also be an energy-conserving or organelle-protective measure, since it may be energetically less costly to extrude than try to degrade all the cargo or avoid overwhelming/jamming the lysosomal pathway. Most of the studies to date have focused on the phenomena and physiological roles of this type of secretion, which often includes various forms of signaling and communication with neighboring cells, but mechanistic analyses have been limited and lagging. For now, the mechanisms governing different stages of even the sensu stricto secretory autophagy, i.e. autophagy-dependent unconventional secretion of leaderless cytosolic protein, are relatively unknown. Further in-depth studies are needed to better understand this collection of pathways of fundamental and applied significance and clearly discern different types as well as define the molecular and cellular machineries and steps that underlie these processes. This area of study, although in its infancy and imperfect at this stage, holds promise for new discoveries and impact.

Summary

  • Mammalian cells have evolved several ways to secrete or extrude cytosolic constituents by autophagy-dependent processes.

  • The mechanisms governing different stages of secretory autophagy are relatively unknown.

  • Secretory autophagy is a less appreciated but emerging alternative termination of the autophagy pathway.

Competing Interests

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

Funding

This work was supported by NIH R01 [grant numbers AI042999 and AI111935] and a center [grant number 1P20GM121176-01].

Abbreviations

     
  • amyloid β

  •  
  • Acb1/AcbA

    acetylCoA binding protein 1/A

  •  
  • ANXA2

    annexin A2

  •  
  • APP

    amyloid precursor protein

  •  
  • ATG

    autophagy-related

  •  
  • BEC

    bladder epithelial cell

  •  
  • DBI

    diazepam binding inhibitor

  •  
  • ER

    endoplasmic reticulum

  •  
  • HBV

    hepatitis B virus

  •  
  • IDE

    insulin-degradating enzyme

  •  
  • IFN-γ

    interferon-γ

  •  
  • IFN-I

    type I interferon

  •  
  • IL-1β

    interleukin-1β

  •  
  • KO

    knockout

  •  
  • LPS

    lipopolysaccharide

  •  
  • MEF

    mouse embryonic fibroblast

  •  
  • MVB

    multivesicular body

  •  
  • TRPML3

    mucolipin TRP channel 3

  •  
  • UPEC

    uropthogenic E. coli

References

References
1
Blobel
G.
and
Dobberstein
B.
(
1975
)
Transfer of proteins across membranes. I. Presence of proteolytically processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of murine myeloma
.
J Cell Biol.
67
,
835
851
2
Rabouille
C.
(
2017
)
Pathways of unconventional protein secretion
.
Trends Cell Biol.
27
,
230
240
3
Suttles
J.
,
Giri
J.G.
and
Mizel
S.B.
(
1990
)
IL-1 secretion by macrophages. Enhancement of IL-1 secretion and processing by calcium ionophores
.
J. Immunol.
144
,
175
182
4
Rubartelli
A.
,
Cozzolino
F.
,
Talio
M.
,
Sitia
R.
(
1990
)
A novel secretory pathway for interleukin-1 beta, a protein lacking a signal sequence
.
EMBO J.
9
,
1503
1510
5
Lamb
C.A.
,
Yoshimori
T.
and
Tooze
S.A.
(
2013
)
The autophagosome: origins unknown, biogenesis complex
.
Nat. Rev. Mol. Cell Biol.
14
,
759
774
6
He
C.
and
Klionsky
D.J.
(
2009
)
Regulation mechanisms and signaling pathways of autophagy
.
Annu. Rev. Genet.
43
,
67
93
7
Zaffagnini
G.
and
Martens
S.
(
2016
)
Mechanisms of selective autophagy
.
J. Mol. Biol.
428
,
1714
1724
8
Mizushima
N.
and
Komatsu
M.
(
2011
)
Autophagy: renovation of cells and tissues
.
Cell
147
,
728
741
9
Stolz
A.
,
Ernst
A.
and
Dikic
I.
(
2014
)
Cargo recognition and trafficking in selective autophagy
.
Nat. Cell Biol.
16
,
495
501
10
Ponpuak
M.
,
Mandell
M.A.
,
Kimura
T.
,
Chauhan
S.
,
Cleyrat
C.
and
Deretic
V.
(
2015
)
Secretory autophagy
.
Curr. Opin. Cell Biol.
35
,
106
116
11
Beale
R.
,
Wise
H.
,
Stuart
A.
,
Ravenhill
B.J.
,
Digard
P.
and
Randow
F.
(
2014
)
A LC3-interacting motif in the influenza A virus M2 protein is required to subvert autophagy and maintain virion stability
.
Cell Host Microbe
15
,
239
247
12
Bel
S.
,
Pendse
M.
,
Wang
Y.
,
Li
Y.
,
Ruhn
K.A.
,
Hassell
B.
et al. 
(
2017
)
Paneth cells secrete lysozyme via secretory autophagy during bacterial infection of the intestine
.
Science
, doi:
13
Buckingham
E.M.
,
Carpenter
J.E.
,
Jackson
W.
and
Grose
C.
(
2014
)
Autophagy and the effects of its inhibition on varicella-zoster virus glycoprotein biosynthesis and infectivity
.
J. Virol.
88
,
890
902
14
Buckingham
E.M.
,
Jarosinski
K.W.
,
Jackson
W.
,
Carpenter
J.E.
and
Grose
C.
(
2016
)
Exocytosis of varicella-zoster virus virions involves a convergence of endosomal and autophagy pathways
.
J. Virol.
90
,
8673
8685
15
Chen
Y.D.
,
Fang
Y.T.
,
Cheng
Y.L.
,
Lin
C.F.
,
Hsu
L.J.
,
Wang
S.Y.
et al. 
(
2017
)
Exophagy of annexin A2 via RAB11, RAB8A and RAB27A in IFN-gamma-stimulated lung epithelial cells
.
Sci. Rep.
7
,
5676
16
Chen
Y.H.
,
Du
W.
,
Hagemeijer
M.C.
,
Takvorian
P.M.
,
Pau
C.
,
Cali
A.
et al. 
(
2015
)
Phosphatidylserine vesicles enable efficient en bloc transmission of enteroviruses
.
Cell
160
,
619
630
17
Cleyrat
C.
,
Darehshouri
A.
,
Steinkamp
M.P.
,
Vilaine
M.
,
Boassa
D.
,
Ellisman
M.H.
et al. 
(
2014
)
Mpl traffics to the cell surface through conventional and unconventional routes
.
Traffic
15
,
961
982
18
Delpeut
S.
,
Rudd
P.A.
,
Labonte
P.
and
von Messling
V.
(
2012
)
Membrane fusion-mediated autophagy induction enhances morbillivirus cell-to-cell spread
.
J. Virol.
86
,
8527
8535
19
Dupont
N.
,
Jiang
S.
,
Pilli
M.
,
Ornatowski
W.
,
Bhattacharya
D.
and
Deretic
V.
(
2011
)
Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1beta
.
EMBO J.
30
,
4701
4711
20
Duran
J.M.
,
Anjard
C.
,
Stefan
C.
,
Loomis
W.F.
and
Malhotra
V.
(
2010
)
Unconventional secretion of Acb1 is mediated by autophagosomes
.
J. Cell Biol.
188
,
527
536
21
Ejlerskov
P.
,
Rasmussen
I.
,
Nielsen
T.T.
,
Bergstrom
A.L.
,
Tohyama
Y.
,
Jensen
P.H.
et al. 
(
2013
)
Tubulin polymerization-promoting protein (TPPP/p25alpha) promotes unconventional secretion of alpha-synuclein through exophagy by impairing autophagosome-lysosome fusion
.
J. Biol. Chem.
288
,
17313
17335
22
Gerstenmaier
L.
,
Pilla
R.
,
Herrmann
L.
,
Herrmann
H.
,
Prado
M.
,
Villafano
G.J.
et al. 
(
2015
)
The autophagic machinery ensures nonlytic transmission of mycobacteria
.
Proc. Natl. Acad. Sci. U.S.A.
112
,
E687
92
23
Granato
M.
,
Santarelli
R.
,
Farina
A.
,
Gonnella
R.
,
Lotti
L.V.
,
Faggioni
A.
et al. 
(
2014
)
Epstein-barr virus blocks the autophagic flux and appropriates the autophagic machinery to enhance viral replication
.
J. Virol.
88
,
12715
12726
24
Griffiths
R.E.
,
Kupzig
S.
,
Cogan
N.
,
Mankelow
T.J.
,
Betin
V.M.
,
Trakarnsanga
K.
et al. 
(
2012
)
Maturing reticulocytes internalize plasma membrane in glycophorin A-containing vesicles that fuse with autophagosomes before exocytosis
.
Blood
119
,
6296
6306
25
Jackson
W.T.
,
Giddings
T.H.
Jr
,
Taylor
M.P.
,
Mulinyawe
S.
,
Rabinovitch
M.
,
Kopito
R.R.
et al. 
(
2005
)
Subversion of cellular autophagosomal machinery by RNA viruses
.
PLoS Biol.
3
,
e156
26
Kimura
T.
,
Jia
J.
,
Kumar
S.
,
Choi
S.W.
,
Gu
Y.
,
Mudd
M.
et al. 
(
2017
)
Dedicated SNAREs and specialized TRIM cargo receptors mediate secretory autophagy
.
EMBO J.
36
,
42
60
27
Kraya
A.A.
,
Piao
S.
,
Xu
X.
,
Zhang
G.
,
Herlyn
M.
,
Gimotty
P.
et al. 
(
2015
)
Identification of secreted proteins that reflect autophagy dynamics within tumor cells
.
Autophagy
11
,
60
74
28
Manjithaya
R.
,
Anjard
C.
,
Loomis
W.F.
and
Subramani
S.
(
2010
)
Unconventional secretion of Pichia pastoris Acb1 is dependent on GRASP protein, peroxisomal functions, and autophagosome formation
.
J. Cell Biol.
188
,
537
546
29
Martins
I.
,
Wang
Y.
,
Michaud
M.
,
Ma
Y.
,
Sukkurwala
A.Q.
,
Shen
S.
et al. 
(
2014
)
Molecular mechanisms of ATP secretion during immunogenic cell death
.
Cell Death Differ.
21
,
79
91
30
Miao
Y.
,
Li
G.
,
Zhang
X.
,
Xu
H.
and
Abraham
S.N.
(
2015
)
A TRP Channel Senses Lysosome Neutralization by Pathogens to Trigger Their Expulsion
.
Cell
161
,
1306
1319
31
Mohl
B.P.
,
Bartlett
C.
,
Mankouri
J.
and
Harris
M.
(
2016
)
Early events in the generation of autophagosomes are required for the formation of membrane structures involved in hepatitis C virus genome replication
.
J. Gen. Virol.
97
,
680
693
32
Nilsson
P.
,
Loganathan
K.
,
Sekiguchi
M.
,
Matsuba
Y.
,
Hui
K.
,
Tsubuki
S.
et al. 
(
2013
)
Abeta secretion and plaque formation depend on autophagy
.
Cell Rep.
5
,
61
69
33
Nowag
H.
,
Guhl
B.
,
Thriene
K.
,
Romao
S.
,
Ziegler
U.
,
Dengjel
J.
et al. 
(
2014
)
Macroautophagy proteins assist epstein barr virus production and get incorporated into the virus particles
.
EBioMedicine
1
,
116
125
34
Ohman
T.
,
Teirila
L.
,
Lahesmaa-Korpinen
A.M.
,
Cypryk
W.
,
Veckman
V.
,
Saijo
S.
et al. 
(
2014
)
Dectin-1 pathway activates robust autophagy-dependent unconventional protein secretion in human macrophages
.
J. Immunol.
192
,
5952
5962
35
Pallet
N.
,
Sirois
I.
,
Bell
C.
,
Hanafi
L.A.
,
Hamelin
K.
,
Dieude
M.
et al. 
(
2013
)
A comprehensive characterization of membrane vesicles released by autophagic human endothelial cells
.
Proteomics
13
,
1108
1120
36
Pastore
N.
,
Brady
O.A.
,
Diab
H.I.
,
Martina
J.A.
,
Sun
L.
,
Huynh
T.
et al. 
(
2016
)
TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages
.
Autophagy
12
,
1240
1258
37
Piccioli
P.
and
Rubartelli
A.
(
2013
)
The secretion of IL-1beta and options for release
.
Semin. Immunol.
25
,
425
429
38
Robinson
S.M.
,
Tsueng
G.
,
Sin
J.
,
Mangale
V.
,
Rahawi
S.
,
McIntyre
L.L.
et al. 
(
2014
)
Coxsackievirus B exits the host cell in shed microvesicles displaying autophagosomal markers
.
PLoS Pathog.
10
,
e1004045
39
Schweers
R.L.
,
Zhang
J.
,
Randall
M.S.
,
Loyd
M.R.
,
Li
W.
,
Dorsey
F.C.
et al. 
(
2007
)
NIX is required for programmed mitochondrial clearance during reticulocyte maturation
.
Proc. Natl. Acad. Sci. U.S.A.
104
,
19500
19505
40
Shrivastava
S.
,
Devhare
P.
,
Sujijantarat
N.
,
Steele
R.
,
Kwon
Y.C.
,
Ray
R.
et al. 
(
2015
)
Knockdown of autophagy inhibits infectious hepatitis C virus release by the exosomal pathway
.
J. Virol.
90
,
1387
1396
41
Sirois
I.
,
Groleau
J.
,
Pallet
N.
,
Brassard
N.
,
Hamelin
K.
,
Londono
I.
et al. 
(
2012
)
Caspase activation regulates the extracellular export of autophagic vacuoles
.
Autophagy
8
,
927
937
42
Son
S.M.
,
Cha
M.Y.
,
Choi
H.
,
Kang
S.
,
Choi
H.
,
Lee
M.S.
et al. 
(
2016
)
Insulin-degrading enzyme secretion from astrocytes is mediated by an autophagy-based unconventional secretory pathway in Alzheimer disease
.
Autophagy
12
,
784
800
43
Starr
T.
,
Child
R.
,
Wehrly
T.D.
,
Hansen
B.
,
Hwang
S.
,
Lopez-Otin
C.
et al. 
(
2012
)
Selective subversion of autophagy complexes facilitates completion of the Brucella intracellular cycle
.
Cell Host Microbe
11
,
33
45
44
Takenouchi
T.
,
Nakai
M.
,
Iwamaru
Y.
,
Sugama
S.
,
Tsukimoto
M.
,
Fujita
M.
et al. 
(
2009
)
The activation of P2X7 receptor impairs lysosomal functions and stimulates the release of autophagolysosomes in microglial cells
.
J. Immunol.
182
,
2051
2062
45
Thorburn
J.
,
Horita
H.
,
Redzic
J.
,
Hansen
K.
,
Frankel
A.E.
and
Thorburn
A.
(
2009
)
Autophagy regulates selective HMGB1 release in tumor cells that are destined to die
.
Cell Death Differ.
16
,
175
183
46
Unuma
K.
,
Aki
T.
,
Funakoshi
T.
,
Hashimoto
K.
and
Uemura
K.
(
2015
)
Extrusion of mitochondrial contents from lipopolysaccharide-stimulated cells: Involvement of autophagy
.
Autophagy
11
,
1520
1536
47
Wang
L.
,
Tian
Y.
and
Ou
J.H.
(
2015
)
HCV induces the expression of Rubicon and UVRAG to temporally regulate the maturation of autophagosomes and viral replication
.
PLoS Pathog.
11
,
e1004764
48
Wang
L.J.
,
Huang
H.Y.
,
Huang
M.P.
,
Liou
W.
,
Chang
Y.T.
,
Wu
C.C.
et al. 
(
2014
)
The microtubule-associated protein EB1 links AIM2 inflammasomes with autophagy-dependent secretion
.
J. Biol. Chem.
289
,
29322
29333
49
Zhang
M.
,
Kenny
S.J.
,
Ge
L.
,
Xu
K.
and
Schekman
R.
(
2015
)
Translocation of interleukin-1beta into a vesicle intermediate in autophagy-mediated secretion
.
Elife
4
,
50
Kimura
T.
,
Jia
J.
,
Claude-Taupin
A.
,
Kumar
S.
,
Choi
S.W.
,
Gu
Y.
et al. 
(
2017
)
Cellular and molecular mechanism for secretory autophagy
.
Autophagy
13
,
1084
1085
51
Marino
G.
,
Pietrocola
F.
,
Eisenberg
T.
,
Kong
Y.
,
Malik
S.A.
,
Andryushkova
A.
et al. 
(
2014
)
Regulation of autophagy by cytosolic acetyl-coenzyme A
.
Mol. Cell
53
,
710
725
52
Munding
C.
,
Keller
M.
,
Niklaus
G.
,
Papin
S.
,
Tschopp
J.
,
Werner
S.
et al. 
(
2006
)
The estrogen-responsive B box protein: a novel enhancer of interleukin-1beta secretion
.
Cell Death Differ.
13
,
1938
1949
53
Berg
T.O.
,
Fengsrud
M.
,
Stromhaug
P.E.
,
Berg
T.
and
Seglen
P.O.
(
1998
)
Isolation and characterization of rat liver amphisomes. Evidence for fusion of autophagosomes with both early and late endosomes
.
J. Biol. Chem.
273
,
21883
21892
54
Ostrowski
M.
,
Carmo
N.B.
,
Krumeich
S.
,
Fanget
I.
,
Raposo
G.
,
Savina
A.
et al. 
(
2010
)
Rab27a and Rab27b control different steps of the exosome secretion pathway
.
Nat. Cell Biol.
12
,
19
30
,
sup pp 1-13
55
Fader
C.M.
,
Sanchez
D.
,
Furlan
M.
and
Colombo
M.I.
(
2008
)
Induction of autophagy promotes fusion of multivesicular bodies with autophagic vacuoles in k562 cells
.
Traffic
9
,
230
250
56
Villarroya-Beltri
C.
,
Baixauli
F.
,
Mittelbrunn
M.
,
Fernandez-Delgado
I.
,
Torralba
D.
,
Moreno-Gonzalo
O.
et al. 
(
2016
)
ISGylation controls exosome secretion by promoting lysosomal degradation of MVB proteins
.
Nat. Commun.
7
,
13588
57
Inoue
J.
,
Krueger
E.W.
,
Chen
J.
,
Cao
H.
,
Ninomiya
M.
and
McNiven
M.A.
(
2015
)
HBV secretion is regulated through the activation of endocytic and autophagic compartments mediated by Rab7 stimulation
.
J. Cell Sci.
128
,
1696
1706
58
Bevins
C.L.
and
Salzman
N.H.
(
2011
)
Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis
.
Nat. Rev. Microbiol.
9
,
356
368
59
Ramanan
D.
and
Cadwell
K.
(
2016
)
Intrinsic defense mechanisms of the intestinal epithelium
.
Cell Host Microbe
19
,
434
441
60
Farre
J.C.
and
Subramani
S.
(
2016
)
Mechanistic insights into selective autophagy pathways: lessons from yeast
.
Nat. Rev. Mol. Cell Biol.
17
,
537
552
61
Bobrie
A.
,
Colombo
M.
,
Raposo
G.
and
Thery
C.
(
2011
)
Exosome secretion: molecular mechanisms and roles in immune responses
.
Traffic
12
,
1659
1668
62
Kimmey
J.M.
and
Stallings
C.L.
(
2016
)
Bacterial Pathogens versus Autophagy: Implications for Therapeutic Interventions
.
Trends Mol. Med.
22
,
1060
1076
63
Jackson
W.T.
(
2015
)
Viruses and the autophagy pathway
.
Virology
479-480
,
450
456
64
Bird
S.W.
,
Maynard
N.D.
,
Covert
M.W.
,
Kirkegaard
K.
(
2014
)
Nonlytic viral spread enhanced by autophagy components
.
Proc. Natl. Acad. Sci. U.S.A.
111
,
13081
13086
,