TitleHumanin is an endogenous activator of chaperone-mediated autophagy.
Publication TypeJournal Article
Year of Publication2018
AuthorsGong Z, Tasset I, Diaz A, Anguiano J, Tas E, Cui L, Kuliawat R, Liu H, Kühn B, Cuervo AMaria, Muzumdar R
JournalJ Cell Biol
Volume217
Issue2
Pagination635-647
Date Published2018 Feb 05
ISSN1540-8140
Abstract

Chaperone-mediated autophagy (CMA) serves as quality control during stress conditions through selective degradation of cytosolic proteins in lysosomes. Humanin (HN) is a mitochondria-associated peptide that offers cytoprotective, cardioprotective, and neuroprotective effects in vivo and in vitro. In this study, we demonstrate that HN directly activates CMA by increasing substrate binding and translocation into lysosomes. The potent HN analogue HNG protects from stressor-induced cell death in fibroblasts, cardiomyoblasts, neuronal cells, and primary cardiomyocytes. The protective effects are lost in CMA-deficient cells, suggesting that they are mediated through the activation of CMA. We identified that a fraction of endogenous HN is present at the cytosolic side of the lysosomal membrane, where it interacts with heat shock protein 90 (HSP90) and stabilizes binding of this chaperone to CMA substrates as they bind to the membrane. Inhibition of HSP90 blocks the effect of HNG on substrate translocation and abolishes the cytoprotective effects. Our study provides a novel mechanism by which HN exerts its cardioprotective and neuroprotective effects.

DOI10.1083/jcb.201606095
Alternate JournalJ. Cell Biol.
PubMed ID29187525
PubMed Central IDPMC5800795
Grant ListR01 AG021904 / AG / NIA NIH HHS / United States
P30 DK041296 / DK / NIDDK NIH HHS / United States
R37 AG021904 / AG / NIA NIH HHS / United States
R01 AG035114 / AG / NIA NIH HHS / United States
P30 AG038072 / AG / NIA NIH HHS / United States
R01 DK098408 / DK / NIDDK NIH HHS / United States
P01 AG031782 / AG / NIA NIH HHS / United States
R56 AG044519 / AG / NIA NIH HHS / United States