Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks.

Abstract

BAG3 is a multi-domain hub that connects two classes of chaperones, small heat shock proteins (sHSPs) via two isoleucine-proline-valine (IPV) motifs and Hsp70 via a BAG domain. Mutations in either the IPV or BAG domain of BAG3 cause a dominant form of myopathy, characterized by protein aggregation in both skeletal and cardiac muscle tissues. Surprisingly, for both disease mutants, impaired chaperone binding is not sufficient to explain disease phenotypes. Recombinant mutants are correctly folded, show unaffected Hsp70 binding but are impaired in stimulating Hsp70-dependent client processing. As a consequence, the mutant BAG3 proteins become the node for a dominant gain of function causing aggregation of itself, Hsp70, Hsp70 clients and tiered interactors within the BAG3 interactome. Importantly, genetic and pharmaceutical interference with Hsp70 binding completely reverses stress-induced protein aggregation for both BAG3 mutations. Thus, the gain of function effects of BAG3 mutants act as Achilles heel of the HSP70 machinery.

• Authors: Melanie Meister-Broekema, Rebecca Freilich, Chandhuru Jagadeesan, Jennifer N Rauch, Rocio Bengoechea, William W Motley, E F Elsiena Kuiper, Melania Minoia, Gabriel V Furtado, Maria A W H van Waarde, Shawn J Bird, Adriana Rebelo, Stephan Zuchner, Peter Pytel, Steven S Scherer, Federica F Morelli, Serena Carra, Conrad C Weihl, Steven Bergink, Jason E Gestwicki, Harm H Kampinga
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 5342 (12 17 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 30559338 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Apoptosis Regulatory Proteins
• BAG3 protein, human
• HSP70 Heat-Shock Proteins

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Apoptosis Regulatory Proteins (genetics)
• Cell Line, Tumor
• HEK293 Cells
• HSP70 Heat-Shock Proteins (metabolism)
• HeLa Cells
• Humans
• Muscle Contraction (genetics, physiology)
• Muscle, Skeletal (pathology)
• Muscular Diseases (genetics, pathology)
• Myocardium (pathology)
• Protein Aggregation, Pathological (genetics, pathology)
• Protein Binding (genetics)