PMID- 29187525 OWN - NLM STAT- MEDLINE DCOM- 20181212 LR - 20240213 IS - 1540-8140 (Electronic) IS - 0021-9525 (Print) IS - 0021-9525 (Linking) VI - 217 IP - 2 DP - 2018 Feb 5 TI - Humanin is an endogenous activator of chaperone-mediated autophagy. PG - 635-647 LID - 10.1083/jcb.201606095 [doi] 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. CI - (c) 2018 Gong et al. FAU - Gong, Zhenwei AU - Gong Z AD - Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA. FAU - Tasset, Inmaculada AU - Tasset I AD - Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY. AD - Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY. FAU - Diaz, Antonio AU - Diaz A AD - Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY. AD - Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY. FAU - Anguiano, Jaime AU - Anguiano J AD - Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY. AD - Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY. FAU - Tas, Emir AU - Tas E AUID- ORCID: 0000-0003-3759-2778 AD - Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA. FAU - Cui, Lingguang AU - Cui L AD - Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY. FAU - Kuliawat, Regina AU - Kuliawat R AUID- ORCID: 0000-0001-8386-2279 AD - Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY. AD - Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY. FAU - Liu, Honghai AU - Liu H AD - Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA. AD - Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA. AD - Division of Cardiology, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA. FAU - Kuhn, Bernhard AU - Kuhn B AD - Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA. AD - Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA. AD - Division of Cardiology, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA. AD - McGowan Institute of Regenerative Medicine, Pittsburgh, PA. FAU - Cuervo, Ana Maria AU - Cuervo AM AUID- ORCID: 0000-0002-0771-700X AD - Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY ana-maria.cuervo@einstein.yu.edu. AD - Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY. FAU - Muzumdar, Radhika AU - Muzumdar R AUID- ORCID: 0000-0003-0284-5536 AD - Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA radhika.muzumdar@chp.edu. LA - eng GR - R01 AG021904/AG/NIA NIH HHS/United States GR - P30 DK041296/DK/NIDDK NIH HHS/United States GR - R37 AG021904/AG/NIA NIH HHS/United States GR - R01 AG035114/AG/NIA NIH HHS/United States GR - P30 DK020541/DK/NIDDK NIH HHS/United States GR - RF1 AG054108/AG/NIA NIH HHS/United States GR - P30 AG038072/AG/NIA NIH HHS/United States GR - R01 DK098408/DK/NIDDK NIH HHS/United States GR - P01 AG031782/AG/NIA NIH HHS/United States GR - R56 AG044519/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20171129 PL - United States TA - J Cell Biol JT - The Journal of cell biology JID - 0375356 RN - 0 (HSP90 Heat-Shock Proteins) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Molecular Chaperones) RN - 0 (humanin) SB - IM MH - Animals MH - *Autophagy MH - Cell Survival MH - Cells, Cultured MH - Cytosol/metabolism MH - HSP90 Heat-Shock Proteins/metabolism MH - Intracellular Signaling Peptides and Proteins/*metabolism MH - Lysosomes/metabolism MH - Male MH - Mice MH - Molecular Chaperones/*metabolism MH - NIH 3T3 Cells MH - Rats MH - Rats, Wistar PMC - PMC5800795 EDAT- 2017/12/01 06:00 MHDA- 2018/12/13 06:00 PMCR- 2018/08/05 CRDT- 2017/12/01 06:00 PHST- 2016/06/21 00:00 [received] PHST- 2017/10/11 00:00 [revised] PHST- 2017/11/06 00:00 [accepted] PHST- 2017/12/01 06:00 [pubmed] PHST- 2018/12/13 06:00 [medline] PHST- 2017/12/01 06:00 [entrez] PHST- 2018/08/05 00:00 [pmc-release] AID - jcb.201606095 [pii] AID - 201606095 [pii] AID - 10.1083/jcb.201606095 [doi] PST - ppublish SO - J Cell Biol. 2018 Feb 5;217(2):635-647. doi: 10.1083/jcb.201606095. Epub 2017 Nov 29.