Humanin is an endogenous activator of chaperonemediated autophagy

Zhenwei Gong, Inmaculada Tasset, Antonio Diaz, Jaime Anguiano, Emir Tas, Lingguang Cui, Regina Kuliawat, Honghai Liu, Bernhard Kühn, Ana Maria Cuervo, Radhika Muzumdar

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)635-647
Number of pages13
JournalJournal of Cell Biology
Issue number2
StatePublished - Feb 1 2018

ASJC Scopus subject areas

  • Cell Biology


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