An Unbiased Screen Identified the Hsp70-BAG3 Complex as a Regulator of Myosin-Binding Protein C3.

Variants in the gene myosin-binding protein C3 ( MYBPC3 ) account for approximately 50% of familial hypertrophic cardiomyopathy (HCM), leading to reduced levels of myosin-binding protein C3 (MyBP-C), the protein product made by gene MYBPC3 . Elucidation of the pathways that regulate MyBP-C protein homeostasis could uncover new therapeutic strategies. Toward this goal, we screened a library of 2,426 bioactive compounds and identified JG98, an allosteric modulator of heat shock protein 70 that inhibits interaction with Bcl-2-associated athanogene (BAG) domain co-chaperones. JG98 reduces MyBP-C protein levels. Furthermore, genetic reduction of BAG3 phenocopies treatment with JG-98 by reducing MYBP-C protein levels.. Thus, an unbiased compound screen identified the heat shock protein 70-BAG3 complex as a regulator of MyBP-C stability.
Competing Interests: This project was funded in part by a grant from the Center for Chemical Genomics at the University of Michigan. Dr Thompson is supported by the National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) (T32 HL007853, K08HL163328). Dr Thompson is also supported by the Protein Folding Disease Initiative and Michigan Biology of Cardiovascular Aging (M-BoCA) at the University of Michigan. Dr Day is supported by the NIH/NHLBI (HL155568), University of Pennsylvania discretionary funding, and a Presidential Professorship. Dr Wagner is supported by an NIH T32 (T32 AR053461) training grant award to the Penn Muscle Institute. Dr Gestwicki is supported by the NIH (NS059690). Dr Ginsburg is a Howard Hughes Medical Institute Investigator and is also supported by the NIH/NHLBI (R35-HL135793). Dr Thompson has received compensation as editor for Merck Manuals. Dr Day is a consultant for Bristol Myers Squibb, Tenaya Therapeutics, and Pfizer. Drs Day and Helms receive support from Bristol Myers Squibb and Pfizer for the SHaRe registry (Sarcomeric Human Cardiomyopathy Registry). Dr Day has received research funding from Lexicon Pharmaceuticals. Dr Helms is a consultant for Tenaya Therapeutics and LEXEO Therapeutics. Dr Gestwicki is a co-founder of Kaizen Therapeutics and a consultant for Faze, Contour, DICE therapeutics, and Protego Biopharma. Dr Ginsburg benefits from patent royalties from Takeda to Boston Children’s Hospital (von Willebrand factor) and the University of Michigan (ADAMTS13) and is a consultant for Equilibra Bioscience. These entities had no role in the preparation of the data presented or approving content of these data. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(© 2023 The Authors.)