Secretory autophagy

Ponpuak, Marisa; Mandell, Michael A.; Kimura, Tomonori; Chauhan, Santosh; Cleyrat, Cédric; Deretic, Vojo

doi:10.1016/j.ceb.2015.04.016

Cited by 421 publications

(385 citation statements)

References 74 publications

(137 reference statements)

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“…Several cellular stresses, e.g., inflammation, nutrient stress, and ER stress, have been reported to trigger secretory autophagy [8,38–40]. In the present study, we demonstrated that oxidative stress induced by 6-OHDA also triggered secretory autophagy.…”

Section: Discussionsupporting

confidence: 75%

“…It is conceivable that some form of autophagic structure (autophagosome, amphisome, or autolysosome) may fuse with the plasma membrane to release the enclosed cytosolic contents into the extracellular space. Indeed, autophagy-mediated unconventional secretion, termed secretory autophagy, has been implicated in the secretion of a subset of unconventionally secreted proteins which include yeast Acb1/DBI, mammalian IL1B, and IDE (insulin degrading enzyme) [8,38–40]. Our study indicates that PARK7 is also secreted via the secretory autophagy.…”

Section: Discussionmentioning

confidence: 73%

“…Although it is known that these unconventionally secreted proteins are released from the cell via an ER-/Golgi-independent pathway, the specific mechanism by which the soluble protein is able to translocate across the hydrophobic plasma membrane still remains to be discussed. Multiple pathways have been proposed as possible routes by which such unconventional secretion might be accomplished, these proposed routes including secretory lysosomes, plasma membrane shedding, exosome derived from multivesicular bodies, and secretory autophagy [1–3,8]. Because some of the proteins that are secreted via the unconventional secretory pathway play important extracellular functional roles in developmental processes and inflammation, the unconventional secretion mechanism is being studied extensively.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…Their size resembles extracellular vesicles and autophagous blebs shed from the plasma membrane, and is distinct from MVB-derived exosomes that are generally much smaller (<150 nm) and similar to eHAV (2,17). Nonetheless, it is not possible to fully exclude a role for autophagy-mediated secretion (29,30) in the biogenesis of quasienveloped eHAV vesicles. Purified eHAV preparations contained no detectable peptides derived from LC3, which in its lipidated LC3-II form is associated with autophagosome membranes.…”

Section: Discussionmentioning

confidence: 99%

Protein composition of the hepatitis A virus quasi-envelope

McKnight

Xie

González‐López

et al. 2017

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

124

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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...

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“…Thakar et al (2010) have demonstrated that the secretion of HDGF is regulated by its N-terminal processing. Autophagy, also called secretory autophagy, was demonstrated to be essential in some kinds of unconventional secretion (Ponpuak et al 2015). Some other DAMPs, E. Effect of chloroquine and quercetin on HDGF level in medium.…”

Section: Discussionmentioning

confidence: 99%

High Serum HDGF Levels Are Predictive of Bone Metastasis and Unfavorable Prognosis in Non-Small Cell Lung Cancer

Zhang

Liu

Chen

et al. 2017

Tohoku J. Exp. Med.

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Hepatoma-derived growth factor (HDGF) is a heparin-binding protein possessing mitogenic activity and could be secreted from necrotic cells passively or actively, thereby functioning as a damage-associated molecular pattern (DAMP). The high expression of HDGF in non-small cell lung cancer (NSCLC) tissues is associated with unfavorable prognosis. However, the clinical significance of serum HDGF has not been elucidated in NSCLC yet. In the present study, we compared the serum levels of HDGF in 235 patients with NSCLC (141 adenocarcinoma and 94 squamous cell carcinoma cases) with those in 40 healthy subjects. Moreover, we explored the correlation between serum HDGF levels and clinicopathologic factors or the overall survival rates. We thus found that the serum HDGF levels were significantly higher in NSCLC patients than those in healthy subjects (P < 0.001). Moreover, there was no significant difference in the serum HDGF levels between adenocarcinoma and squamous cell carcinoma. Importantly, the higher serum levels of HDGF were significantly associated with bone metastasis and with lower overall survival rates. Thus, serum HDGF was identified as an independent prognostic factor indicating poor prognosis of NSCLC. Using A549 human lung adenocarcinoma cell line, we demonstrated that an autophagy inhibitor, chloroquine, could inhibit the HDGF secretion, while quercetin, an autophagy inducer derived from a traditional Chinese drug, could facilitate HDGF secretion. In conclusion, high serum levels of HDGF were significantly correlated to bone metastasis and poorer prognosis of NSCLC. We suggest that anti-HDGF therapy is potential to protect NSCLC patients with advanced stages from bone metastasis.

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Secretory autophagy

Cited by 421 publications

References 74 publications

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

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

Protein composition of the hepatitis A virus quasi-envelope

High Serum HDGF Levels Are Predictive of Bone Metastasis and Unfavorable Prognosis in Non-Small Cell Lung Cancer

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