BAG3: Nature's Quintessential Multi-Functional Protein Functions as a Ubiquitous Intra-Cellular Glue

Caitlyn M Brenner; Muaaz Choudhary; Michael G McCormick; David Cheung; Gavin P Landesberg; Ju-Fang Wang; Jianliang Song; Thomas G Martin; Joseph Y Cheung; Hui-Qi Qu; Hakon Hakonarson; Arthur M Feldman

doi:10.3390/cells12060937

BAG3: Nature's Quintessential Multi-Functional Protein Functions as a Ubiquitous Intra-Cellular Glue

Cells. 2023 Mar 19;12(6):937. doi: 10.3390/cells12060937.

Authors

Caitlyn M Brenner¹, Muaaz Choudhary¹, Michael G McCormick^{1

2}, David Cheung^{1

2}, Gavin P Landesberg^{1

2}, Ju-Fang Wang^{1

2}, Jianliang Song^{1

2}, Thomas G Martin³, Joseph Y Cheung⁴, Hui-Qi Qu⁵, Hakon Hakonarson^{5

6

7

8}, Arthur M Feldman^{1

2}

Affiliations

¹ Department of Medicine, Division of Cardiology, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, MERB 752, Philadelphia, PA 19140, USA.
² Center for Neurovirology and Gene Editing, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
³ Department of Molecular, Cellular and Developmental Biology, Colorado University School of Medicine, Aurora, CO 80045, USA.
⁴ Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁵ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 191104, USA.
⁶ Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 191104, USA.
⁷ Division of Human Genetics and Division of Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 191104, USA.
⁸ Department of Pediatrics, Division of Human Genetics and Division of Pulmonary Medicine, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 191104, USA.

Abstract

BAG3 is a 575 amino acid protein that is found throughout the animal kingdom and homologs have been identified in plants. The protein is expressed ubiquitously but is most prominent in cardiac muscle, skeletal muscle, the brain and in many cancers. We describe BAG3 as a quintessential multi-functional protein. It supports autophagy of both misfolded proteins and damaged organelles, inhibits apoptosis, maintains the homeostasis of the mitochondria, and facilitates excitation contraction coupling through the L-type calcium channel and the beta-adrenergic receptor. High levels of BAG3 are associated with insensitivity to chemotherapy in malignant cells whereas both loss of function and gain of function variants are associated with cardiomyopathy.

Keywords: BAG3; apoptosis; autophagy; cellular inhibitor of activation protein cIAP; excitation contraction coupling; heart; mitochondria; mitochondrial uniporter.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Adaptor Proteins, Signal Transducing* / genetics
Adaptor Proteins, Signal Transducing* / metabolism
Animals
Apoptosis
Apoptosis Regulatory Proteins* / genetics
Apoptosis Regulatory Proteins* / metabolism
Cytoplasm / metabolism
Myocardium / metabolism

Substances

Adaptor Proteins, Signal Transducing
Apoptosis Regulatory Proteins
BAG3 protein, human

Grants and funding

This study was supported by an SRA from Renovacor, Inc. Boston, MA, (A.M.F.) Institutional Development Funds from the Children’s Hospital of Philadelphia to the Center for Applied Genomics and the Children’s Hospital of Philadelphia Endowed Chair in Genomic Research (H.H.). Grant/award number not applicable. The authors also thank investigators in Salerno Italy, Mainz Germany, Chicago Illinois and San Diego California who have been kind enough to share their reagents, mice, expertise, and time as we all work to move BAG3 technology from mice to humans with BAG3-related disease.