TY - JOUR
T1 - Humanin is an endogenous activator of chaperonemediated autophagy
AU - Gong, Zhenwei
AU - Tasset, Inmaculada
AU - Diaz, Antonio
AU - Anguiano, Jaime
AU - Tas, Emir
AU - Cui, Lingguang
AU - Kuliawat, Regina
AU - Liu, Honghai
AU - Kühn, Bernhard
AU - Cuervo, Ana Maria
AU - Muzumdar, Radhika
N1 - Publisher Copyright:
© 2018 Gong et al.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - 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.
AB - 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.
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U2 - 10.1083/jcb.201606095
DO - 10.1083/jcb.201606095
M3 - Article
C2 - 29187525
AN - SCOPUS:85041697542
SN - 0021-9525
VL - 217
SP - 635
EP - 647
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 2
ER -