Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy

• Published in: The Journal of clinical investigation Vol. 130; no. 8; pp. 4470 - 4485
• Main Authors: Bengoechea, Rocio, Findlay, Andrew R, Bhadra, Ankan K, Shao, Hao, Stein, Kevin C, Pittman, Sara K, Daw, Jil Aw, Gestwicki, Jason E, True, Heather L, Weihl, Conrad C
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.08.2020
• Subjects: Animal models; Animals; Biomedical research; Cell culture; Disease; Disease Models, Animal; Gain of Function Mutation; Genetic aspects; Heat shock proteins; HeLa Cells; HSP40 Heat-Shock Proteins - antagonists & inhibitors; HSP40 Heat-Shock Proteins - genetics; HSP40 Heat-Shock Proteins - metabolism; HSP70 Heat-Shock Proteins - antagonists & inhibitors; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Hsp70 protein; Humans; Mice; Molecular Chaperones - antagonists & inhibitors; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Molecular modelling; Muscle Strength - genetics; Muscular Dystrophies, Limb-Girdle - drug therapy; Muscular Dystrophies, Limb-Girdle - genetics; Muscular Dystrophies, Limb-Girdle - metabolism; Muscular Dystrophies, Limb-Girdle - pathology; Muscular dystrophy; Musculoskeletal system; Mutation; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Propagation; Protein interaction; Proteins; Quality control; Saccharomyces cerevisiae; Skeletal muscle; Toxicity; Muscle Biology; Protein misfolding; Chaperones; Skeletal muscle; Cell Biology
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/jci136167

Dominant mutations in the HSP70 cochaperone DNAJB6 cause a late-onset muscle disease termed limb-girdle muscular dystrophy type D1 (LGMDD1), which is characterized by protein aggregation and vacuolar myopathology. Disease mutations reside within the G/F domain of DNAJB6, but the molecular mechanisms underlying dysfunction are not well understood. Using yeast, cell culture, and mouse models of LGMDD1, we found that the toxicity associated with disease-associated DNAJB6 required its interaction with HSP70 and that abrogating this interaction genetically or with small molecules was protective. In skeletal muscle, DNAJB6 localizes to the Z-disc with HSP70. Whereas HSP70 normally diffused rapidly between the Z-disc and sarcoplasm, the rate of diffusion of HSP70 in LGMDD1 mouse muscle was diminished, probably because it had an unusual affinity for the Z-disc and mutant DNAJB6. Treating LGMDD1 mice with a small-molecule inhibitor of the DNAJ-HSP70 complex remobilized HSP70, improved strength, and corrected myopathology. These data support a model in which LGMDD1 mutations in DNAJB6 are a gain-of-function disease that is, counterintuitively, mediated via HSP70 binding. Thus, therapeutic approaches targeting HSP70-DNAJB6 may be effective in treating this inherited muscular dystrophy.