Unconventional secretion of Acb1 is mediated by autophagosomes

Durán, Juan M.; Anjard, Christophe; Stefan, Christopher J.; Loomis, William F.; Malhotra, Vivek

doi:10.1083/jcb.200911154

Cited by 367 publications

(453 citation statements)

References 51 publications

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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%

“…To gain insight into the mechanism by which 6-OHDA treatment increased PARK7 secretion, we examined whether 6-OHDA induced autophagy, since it had recently been shown that the secretion of several proteins lacking a signal sequence is associated with the autophagy-based unconventional secretory pathway [38–40]. To exclude any possible effect of incubation of cells in serum-free medium on monitoring of autophagy induction, autophagic flux was evaluated using the lysate from the cells treated with 6-OHDA for 3 h. By monitoring the conversion of MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta) from a cytosolic form (LC3B-I) to its lipidated phagophore- and autophagosome-associated form (LC3B-II), we found that 6-OHDA treatment induced increase in LC3B-II levels in SH-SY5Y cells (Figure 4(A)).

10.1080/15548627.2018.1493043-F0004Figure 4.6-OHDA treatment induced autophagy in SH-SY5Y cells and WT MEF cells.…”

Section: Resultsmentioning

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%

10.1080/15548627.2018.1493043-F0004Figure 4.6-OHDA treatment induced autophagy in SH-SY5Y cells and WT MEF cells.…”

Section: Resultsmentioning

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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“…Extracellular conversion of a protein precursor into signaling peptides has also been observed in the distantly related dictyostelid Polysphondylium pallidum and the yeasts Pichia pastoris and Saccharomyces cerevisiae, as well as mammalian astrocytes (14,15,27,29). In Pichia, the SDF-2-like activity produced from the ACB1 precursor is required for quorum sensing to regulate sporulation (29).…”

Section: Discussionmentioning

confidence: 97%

The Polyketide MPBD Initiates the SDF-1 Signaling Cascade That Coordinates Terminal Differentiation in Dictyostelium

Anjard

Loomis

2011

Eukaryot Cell

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Dictyostelium uses a wide array of chemical signals to coordinate differentiation as it switches from a unicellular to a multicellular organism. MPBD, the product of the polyketide synthase encoded by stlA, regulates stalk and spore differentiation by rapidly stimulating the release of the phosphopeptide SDF-1. By analyzing specific mutants affected in MPBD or SDF-1 production, we delineated a signal transduction cascade through the membrane receptor CrlA coupled to G␣1, leading to the inhibition of GskA so that the precursor of SDF-1 is released. It is then processed by the extracellular protease of TagB on prestalk cells. SDF-1 apparently acts through the adenylyl cyclase ACG to activate the cyclic AMP (cAMP)-dependent protein kinase A (PKA) and trigger the production of more SDF-1. This signaling cascade shows similarities to the SDF-2 signaling pathway, which acts later to induce rapid spore encapsulation.

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“…Studies have primarily focused on autophagy in unconventional secretion, a collection of processes through which certain proteins are secreted from cells either via direct trafficking from the endoplasmic reticulum (ER) to the plasma membrane in a Golgi-independent manner, or via the transport of cytoplasmic proteins lacking an amino-terminal ER signal sequence to the cell surface, completely bypassing the ER-Golgi route 126 . Autophagy-related proteins (ATGs) have been genetically implicated in the unconventional secretion of the acyl-CoA-binding protein Acb1 in yeast (AcbA in Dictyostelium discoideum), and inflammatory mediators such as interleukin-1β (IL-1β) and IL-18, the high mobility group protein B1 (HMGB1) and the integral membrane protein ΔF508 CFTR (cystic fibrosis transmembrane conductance regulator) in mammalian cells [127][128][129][130][131] . The unconventional secretion of these proteins is also dependent on Golgi membrane-binding proteins of the GRASP family in both yeast and mammals 129,130,132 .…”

Section: Box 2 | Autophagy and Secretionmentioning

confidence: 99%