TitleLoss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy
AuthorsFang, Xi
Bogomolovas, Julius
Wu, Tongbin
Zhang, Wei
Liu, Canzhao
Veevers, Jennifer
Stroud, Matthew J.
Zhang, Zhiyuan
Ma, Xiaolong
Mu, Yongxin
Lao, Dieu-Hung
Dalton, Nancy D.
Gu, Yusu
Wang, Celine
Wang, Michael
Liang, Yan
Lange, Stephan
Ouyang, Kunfu
Peterson, Kirk L.
Evans, Sylvia M.
Chen, Ju
AffiliationUCSD, Dept Med, La Jolla, CA USA.
Heidelberg Univ, Cent Inst Mental Hlth, Med Fac Mannheim, Dept Cognit & Clin Neurosci, Mannheim, Germany.
Cent S Univ, Xiangya Hosp 2, Dept Cardiothorac Surg, Changsha, Hunan, Peoples R China.
Peking Univ, Shenzhen Grad Sch, Drug Discovery Ctr, Key Lab Chem Genom, Shenzhen, Peoples R China.
UCSD, Dept Pharmacol, La Jolla, CA USA.
UCSD, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA USA.
Univ Calif San Diego, Sch Med, 9500 Gilman Dr,M-C 0613C, La Jolla, CA 92093 USA.
KeywordsHEAT-SHOCK PROTEINS
DILATED CARDIOMYOPATHY
IN-VIVO
CARDIAC-HYPERTROPHY
HEAT-SHOCK-PROTEIN-70 HSP70
MOLECULAR CHAPERONES
INCLUSION-BODIES
FAMILY PROTEINS
TRANSGENIC MICE
EARLY LETHALITY
Issue Date2017
PublisherJOURNAL OF CLINICAL INVESTIGATION
CitationJOURNAL OF CLINICAL INVESTIGATION.2017,127(8),3189-3200.
AbstractDefective protein quality control (PQC) systems are implicated in multiple diseases. Molecular chaperones and co-chaperones play a central role in functioning PQC. Constant mechanical and metabolic stress in cardiomyocytes places great demand on the PQC system. Mutation and downregulation of the co-chaperone protein BCL-2-associated athanogene 3 (BAG3) are associated with cardiac myopathy and heart failure, and a BAG3 E455K mutation leads to dilated cardiomyopathy (DCM). However, the role of BAG3 in the heart and the mechanisms by which the E455K mutation leads to DCM remain obscure. Here, we found that cardiac-specific Bag3-KO and E455K-knockin mice developed DCM. Comparable phenotypes in the 2 mutants demonstrated that the E455K mutation resulted in loss of function. Further experiments revealed that the E455K mutation disrupted the interaction between BAG3 and HSP70. In both mutants, decreased levels of small heat shock proteins (sHSPs) were observed, and a subset of proteins required for cardiomyocyte function was enriched in the insoluble fraction. Together, these observations suggest that interaction between BAG3 and HSP70 is essential for BAG3 to stabilize sHSPs and maintain cardiomyocyte protein homeostasis. Our results provide insight into heart failure caused by defects in BAG3 pathways and suggest that increasing BAG3 protein levels may be of therapeutic benefit in heart failure.
URIhttp://hdl.handle.net/20.500.11897/471804
ISSN0021-9738
DOI10.1172/JCI94310
IndexedSCI(E)
Appears in Collections:深圳研究生院待认领

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