TitleA BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress.
Publication TypeJournal Article
Year of Publication2017
AuthorsJudge LM, Perez-Bermejo JA, Truong A, Ribeiro AJs, Yoo JC, Jensen CL, Mandegar MA, Huebsch N, Kaake RM, So P-L, Srivastava D, Pruitt BL, Krogan NJ, Conklin BR
JournalJCI Insight
Volume2
Issue14
Date Published2017 Jul 20
ISSN2379-3708
Abstract

Molecular chaperones regulate quality control in the human proteome, pathways that have been implicated in many diseases, including heart failure. Mutations in the BAG3 gene, which encodes a co-chaperone protein, have been associated with heart failure due to both inherited and sporadic dilated cardiomyopathy. Familial BAG3 mutations are autosomal dominant and frequently cause truncation of the coding sequence, suggesting a heterozygous loss-of-function mechanism. However, heterozygous knockout of the murine BAG3 gene did not cause a detectable phenotype. To model BAG3 cardiomyopathy in a human system, we generated an isogenic series of human induced pluripotent stem cells (iPSCs) with loss-of-function mutations in BAG3. Heterozygous BAG3 mutations reduced protein expression, disrupted myofibril structure, and compromised contractile function in iPSC-derived cardiomyocytes (iPS-CMs). BAG3-deficient iPS-CMs were particularly sensitive to further myofibril disruption and contractile dysfunction upon exposure to proteasome inhibitors known to cause cardiotoxicity. We performed affinity tagging of the endogenous BAG3 protein and mass spectrometry proteomics to further define the cardioprotective chaperone complex that BAG3 coordinates in the human heart. Our results establish a model for evaluating protein quality control pathways in human cardiomyocytes and their potential as therapeutic targets and susceptibility factors for cardiac drug toxicity.

DOI10.1172/jci.insight.94623
Alternate JournalJCI Insight
PubMed ID28724793
PubMed Central IDPMC5518554
Grant ListP01 HL089707 / HL / NHLBI NIH HHS / United States
U01 HL100406 / HL / NHLBI NIH HHS / United States
R01 HL130533 / HL / NHLBI NIH HHS / United States
R01 HL135358 / HL / NHLBI NIH HHS / United States
K12 HD072222 / HD / NICHD NIH HHS / United States
T32 HL007544 / HL / NHLBI NIH HHS / United States