Dedicated
            <scp>SNARE</scp>
            s and specialized
            <scp>TRIM</scp>
            cargo receptors mediate secretory autophagy

Kimura, Tomonori; Jia, Jingyue; Kumar, Suresh; Choi, Su-Mi; Gu, Yuexi; Mudd, Michal H.; Dupont, Nicolas; Jiang, Shanya; Peters, Ryan; Farzam, Farzin; Jain, Ashish; Lidke, Keith A.; Adams, Christopher M.; Johansen, Terje; Deretić, Vojo

doi:10.15252/embj.201695081

Cited by 274 publications

(328 citation statements)

References 98 publications

(227 reference statements)

Supporting

Mentioning

319

Contrasting

Order By: Relevance

“…Purified eHAV preparations contained no detectable peptides derived from LC3, which in its lipidated LC3-II form is associated with autophagosome membranes. However, LC3 appears to be difficult to detect by mass spectrometry in autophagosome-derived extracellular vesicles (31,32). Nonetheless, eHAV vesicles were not precipitated by anti-LC3 antibody (Fig.…”

Section: Discussionmentioning

confidence: 96%

Protein composition of the hepatitis A virus quasi-envelope

McKnight

Xie

González‐López

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

124

View full text Add to dashboard Cite

The Picornaviridae are a diverse family of RNA viruses including many pathogens of medical and veterinary importance. Classically considered "nonenveloped," recent studies show that some picornaviruses, notably hepatitis A virus (HAV; genus Hepatovirus) and some members of the Enterovirus genus, are released from cells nonlytically in membranous vesicles. To better understand the biogenesis of quasienveloped HAV (eHAV) virions, we conducted a quantitative proteomics analysis of eHAV purified from cell-culture supernatant fluids by isopycnic ultracentrifugation. Amino acid-coded mass tagging (AACT) with stable isotopes followed by tandem mass spectrometry sequencing and AACT quantitation of peptides provided unambiguous identification of proteins associated with eHAV versus unrelated extracellular vesicles with similar buoyant density. Multiple peptides were identified from HAV capsid proteins (53.7% coverage), but none from nonstructural proteins, indicating capsids are packaged as cargo into eHAV vesicles via a highly specific sorting process. Other eHAVassociated proteins (n = 105) were significantly enriched for components of the endolysosomal system (>60%, P < 0.001) and included many common exosome-associated proteins such as the tetraspanin CD9 and dipeptidyl peptidase 4 (DPP4) along with multiple endosomal sorting complex required for transport III (ESCRT-III)-associated proteins. Immunoprecipitation confirmed that DPP4 is displayed on the surface of eHAV produced in cell culture or present in sera from humans with acute hepatitis A. No LC3-related peptides were identified by mass spectrometry. RNAi depletion studies confirmed that ESCRT-III proteins, particularly CHMP2A, function in eHAV biogenesis. In addition to identifying surface markers of eHAV vesicles, the results support an exosome-like mechanism of eHAV egress involving endosomal budding of HAV capsids into multivesicular bodies.exosome | multivesicular body | ESCRT | extracellular vesicle | picornavirus T he Picornaviridae are a large and diverse family of positivestrand RNA viruses that include numerous pathogens (1). Classically considered "nonenveloped," these viruses package their single-stranded genomes within stable icosahedral protein capsids that are released from cells following cell lysis. However, recent work has revealed that several picornaviruses gain egress from cells in a nonlytic fashion within the lumen of extracellular vesicles shed from the cell. Most notably, hepatitis A virus (HAV; genus Hepatovirus), an important cause of enterically transmitted hepatitis in humans, replicates without cytopathic effect and is released from cells as membrane-wrapped, "quasienveloped" (eHAV) virions similar in size and density to exosomes (2). eHAV virions have been identified in sera collected from persons with acute hepatitis A, as well as in supernatant fluids of infected cell cultures. These virions are completely cloaked in host-derived membranes that protect the capsid from neutralizing antibody until the quasi-envelope is degraded wi...

show abstract

Section: Discussionmentioning

confidence: 96%

Protein composition of the hepatitis A virus quasi-envelope

McKnight

Xie

González‐López

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

124

View full text Add to dashboard Cite

show abstract

“…For example, recruitment of the autophagy machinery by the activated AIM2 inflammasome has been proposed to mediate the release of IL-1β via exocytosis of the autophagosome [32]. Thus, IL-1β can be released in an autophagy-dependent manner that requires SNAREs and syntaxins [33]. Additional studies showed that autophagy is required for the release of active IL-1β or IL-18 downstream of other inflammasomes [34].…”

Section: Crosstalk Between Autophagy and The Inflammasome Machineriesmentioning

confidence: 99%

Checks and Balances between Autophagy and Inflammasomes during Infection

Seveau

Turner

Gavrilin

et al. 2018

Journal of Molecular Biology

View full text Add to dashboard Cite

Autophagy and inflammasome complex assembly are physiological processes that control homeostasis, inflammation, and immunity. Autophagy is a ubiquitous pathway that degrades cytosolic macromolecules or organelles, as well as intracellular pathogens. Inflammasomes are multi-protein complexes that assemble in the cytosol of cells upon detection of pathogen- or danger-associated molecular patterns. A critical outcome of inflammasome assembly is the activation of the serine protease caspase-1, which activates the pro-inflammatory cytokine precursors pro-IL-1β and pro-IL-18. Studies on chronic inflammatory diseases, heart diseases, Alzheimer's disease, and multiple sclerosis revealed that autophagy and inflammasomes intersect and regulate each other. In the context of infectious diseases, however, less is known about the interplay between autophagy and inflammasome assembly, although it is becoming evident that pathogens have evolved multiple strategies to inhibit and/or subvert these pathways and to take advantage of their intricate crosstalk. An improved appreciation of these pathways and their subversion by diverse pathogens is expected to help in the design of anti-infective therapeutic interventions.

show abstract

“…In future studies, it would also be of interest to evaluate whether other known key proteins involved in secretory autophagy, such as RAB8A (RAB8A, member RAS oncogene family) and GORASP2/GRASP55 (golgi reassembly stacking protein 2) [39,40], are implicated in PARK7 secretion, and whether 6-OHDA-induced secretory autophagy is implicated in the secretion of other proteins. It has been recently reported that dedicated SNAREs participate in secretory autophagy-mediated unconventional secretion of IL1B in response to lysosome damage [56]. Interestingly, secretion of IL1B depends on plasma membrane STX3 (syntaxin 3) and STX4 (syntaxin 4) instead of delivery to lysosomes via STX17 (syntaxin 17), which has been identified as a necessary protein for autophagosomal fusion with the endosome/lysosome [57].…”

Section: Discussionmentioning

confidence: 99%

6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway

et al. 2018

View full text Add to dashboard Cite

PARK7/DJ-1 is a Parkinson disease- and cancer-associated protein that functions as a multifunctional protein involved in gene transcription regulation and anti-oxidative defense. Although PARK7 lacks the secretory signal sequence, it is secreted and plays important physiological and pathophysiological roles. Whereas secretory proteins that lack the endoplasmic reticulum-targeting signal sequence are secreted from cells by way of what is called the unconventional secretion mechanism, the specific processes responsible for causing PARK7 to be secreted across the plasma membrane have remained unclear. In the present study, we found that PARK7 secretion was increased by treatment with 6-OHDA via the unconventional secretory pathway in human neuroblastoma SH-SY5Y cells and MEF cells. We also found that 6-OHDA-induced PARK7 secretion was suppressed in Atg5-, Atg9-, or Atg16l1-deficient MEF cells or ATG16L1 knockdown SH-SY5Y cells, indicating that the autophagy-based unconventional secretory pathway is involved in PARK7 secretion. We moreover observed that 6-OHDA-derived electrophilic quinone induced oxidative stress as indicated by a decrease in glutathione levels, and that this was suppressed by pretreatment with antioxidant NAC. We further found that NAC treatment suppressed autophagy and PARK7 secretion. We also observed that 6-OHDA-induced autophagy was associated with activation of AMPK and ULK1 via a pathway which was independent of MTOR. Collectively these results suggest that electrophilic 6-OHDA quinone enhances oxidative stress, and that this is followed by AMPK-ULK1 pathway activation and induction of secretory autophagy to produce unconventional secretion of PARK7.Abbreviations: 6-OHDA: 6-hydroxydopamine; AMPK: AMP-activated protein kinase; ATG: autophagy related; CAV1: caveolin 1; ER: endoplasmic reticulum; FN1: fibronectin 1; GSH: glutathione; IDE: insulin degrading enzyme; IL: interleukin; LDH: lactate dehydrogenase; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetyl-L-cysteine; PARK7/DJ-1: Parkinsonism associated deglycase; PD: Parkinson disease; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; RPN1: ribophorin I; ROS: reactive oxygen species; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type

show abstract

Dedicated SNARE s and specialized TRIM cargo receptors mediate secretory autophagy

Cited by 274 publications

References 98 publications

Protein composition of the hepatitis A virus quasi-envelope

Protein composition of the hepatitis A virus quasi-envelope

Checks and Balances between Autophagy and Inflammasomes during Infection

6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway

Contact Info

Product

Resources

About