Humanin is an endogenous activator of chaperone-mediated autophagy. Academic Article uri icon

Overview

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.

publication date

  • November 29, 2017

Research

keywords

  • Autophagy
  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones

Identity

PubMed Central ID

  • PMC5800795

Scopus Document Identifier

  • 85041697542

Digital Object Identifier (DOI)

  • 10.1083/jcb.201606095

PubMed ID

  • 29187525

Additional Document Info

volume

  • 217

issue

  • 2