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

• Published in: Nature communications Vol. 9; no. 1; pp. 5342 - 14
• Main Authors: Meister-Broekema, Melanie, Freilich, Rebecca, Jagadeesan, Chandhuru, Rauch, Jennifer N., Bengoechea, Rocio, Motley, William W., Kuiper, E. F. Elsiena, Minoia, Melania, Furtado, Gabriel V., van Waarde, Maria A. W. H., Bird, Shawn J., Rebelo, Adriana, Zuchner, Stephan, Pytel, Peter, Scherer, Steven S., Morelli, Federica F., Carra, Serena, Weihl, Conrad C., Bergink, Steven, Gestwicki, Jason E., Kampinga, Harm H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.12.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 13/31; 13/44; 13/51; 13/89; 14/1; 14/19; 14/63; 45/23; 631/337/470/1981; 631/45/470/1981; 692/4017; 82/29; 82/51; 82/80; 82/83; Adaptor Proteins, Signal Transducing - genetics; Agglomeration; Apoptosis Regulatory Proteins - genetics; Binding; Cardiac muscle; Cell Line, Tumor; Chaperones; Heat shock; Heat shock proteins; HEK293 Cells; HeLa Cells; HSP70 Heat-Shock Proteins - metabolism; Hsp70 protein; Humanities and Social Sciences; Humans; Isoleucine; multidisciplinary; Muscle Contraction - genetics; Muscle Contraction - physiology; Muscle, Skeletal - pathology; Muscles; Muscular Diseases - genetics; Muscular Diseases - pathology; Mutants; Mutation; Myocardium - pathology; Myopathy; Phenotypes; Proline; Protein Aggregation, Pathological - genetics; Protein Aggregation, Pathological - pathology; Protein Binding - genetics; Protein interaction; Proteins; Science; Science (multidisciplinary); Skeletal muscle; Small heat shock proteins; Stalling; Valine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07718-5

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. BAG3 is a Hsp70 co-chaperone that is highly expressed in muscles. Here the authors show that several myofibrillar myopathy causing BAG3 mutations are not impaired in Hsp70 binding, but rather impair the ADP-ATP exchange step of the Hsp70 cycle, causing the aggregation of BAG3, Hsp70 and Hsp70 clients and leading to a collapse of protein homeostasis.