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

Andrea D Thompson; Marcus J Wagner; Juliani Rodriguez; Alok Malhotra; Steve Vander Roest; Ulla Lilienthal; Hao Shao; Mathav Vignesh; Keely Weber; Jaime M Yob; Benjamin L Prosser; Adam S Helms; Jason E Gestwicki; David Ginsburg; Sharlene M Day

doi:10.1016/j.jacbts.2023.04.009

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

JACC Basic Transl Sci. 2023 Aug 2;8(9):1198-1211. doi: 10.1016/j.jacbts.2023.04.009. eCollection 2023 Sep.

Authors

Andrea D Thompson¹, Marcus J Wagner², Juliani Rodriguez¹, Alok Malhotra¹, Steve Vander Roest³, Ulla Lilienthal¹, Hao Shao⁴, Mathav Vignesh¹, Keely Weber¹, Jaime M Yob², Benjamin L Prosser⁵, Adam S Helms¹, Jason E Gestwicki⁴, David Ginsburg^{6

7

8

9

10}, Sharlene M Day²

Affiliations

¹ Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
² Department of Internal Medicine, Division of Cardiovascular Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³ Center for Chemical Genomics, Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
⁴ Institute for Neurodegenerative Diseases and Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA.
⁵ Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁶ Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
⁷ Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
⁸ Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
⁹ Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
¹⁰ The Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.

Abstract

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.

Keywords: BAG3; MYBPC3; hypertrophic cardiomyopathy; molecular chaperones.

Abstract

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