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RNA sequencing revealed extensive baseline changes in chaperone- and stress response protein\u2013encoding genes, and protein levels of key BAG3 binding partners were perturbed. Molecular dynamics simulations of the BAG3-HSC70 complex predicted a partial disengagement by the R477H mutation. In line with this, BAG3-R477H bound less HSC70 than BAG3-WT in coimmunoprecipitation assays. Finally, myofibrillar disarray triggered by proteasome inhibition in R477H cells was mitigated by overexpression of the stress response protein heat shock factor 1 (HSF1). These studies reveal the importance of BAG3 in coordinating protein quality control subsystem usage within the cardiomyocyte and suggest that augmenting HSF1 activity might be beneficial as a means to mitigate proteostatic stress in the context of BAG3-associated DCM.<\/jats:p>","DOI":"10.1172\/jci.insight.128799","type":"journal-article","created":{"date-parts":[[2019,11,13]],"date-time":"2019-11-13T11:01:11Z","timestamp":1573642871000},"source":"Crossref","is-referenced-by-count":42,"title":["Investigation of a dilated cardiomyopathy\u2013associated variant in BAG3 using genome-edited iPSC-derived cardiomyocytes"],"prefix":"10.1172","volume":"4","author":[{"given":"Chris","family":"McDermott-Roe","sequence":"first","affiliation":[{"name":"Division of Cardiology and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 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