4.7 Article

Secretory autophagy maintains proteostasis upon lysosome inhibition

Journal

JOURNAL OF CELL BIOLOGY
Volume 221, Issue 6, Pages -

Publisher

ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.202110151

Keywords

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Categories

Funding

  1. National Institutes of Health [CA201849, CA126792, CA213775, AG057462, CA226851, F31CA217015]
  2. Samuel Waxman Cancer Research Foundation
  3. Mark Foundation for Cancer Research
  4. University of California, San Francisco QB3 Calico Longevity Fellowship
  5. Dale Frey Breakthrough Award from the Damon Runyon Cancer Research Foundation [DFS 14-15]
  6. Banting Postdoctoral Fellowship [201409BPF-335868]
  7. Cancer Research Society Award [22805]
  8. National Science Foundation Graduate Student Fellowship [1650113]

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The endolysosome system is involved in autophagic degradation and secretory pathways, including the release of extracellular vesicles and particles (EVPs). This study reveals a secretory autophagy pathway that is upregulated during endolysosome inhibition and mediates the release of autophagic cargo receptors via EVPs. This secretion process is regulated by multiple ATGs and the small GTPase Rab27a.
The endolysosome system plays central roles in both autophagic degradation and secretory pathways, including the release of extracellular vesicles and particles (EVPs). Although previous work reveals important interconnections between autophagy and EVP-mediated secretion, our understanding of these secretory events during endolysosome inhibition remains incomplete. Here, we delineate a secretory autophagy pathway upregulated in response to endolysosomal inhibition, which mediates EVP-associated release of autophagic cargo receptors, including p62/SQSTM1. This secretion is highly regulated and dependent on multiple ATGs required for autophagosome formation, as well as the small GTPase Rab27a. Furthermore, disrupting autophagosome maturation, either via genetic inhibition of autophagosome-to-autolysosome fusion or expression of SARS-CoV-2 ORF3a, is sufficient to induce EVP secretion of autophagy cargo receptors. Finally, ATG-dependent EVP secretion buffers against the intracellular accumulation of autophagy cargo receptors when classical autophagic degradation is impaired. Thus, we propose secretory autophagy via EVPs functions as an alternate route to clear sequestered material and maintain proteostasis during endolysosomal dysfunction or impaired autophagosome maturation.

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