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Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle

ABSTRACT: Muscle contraction is driven by the molecular machinery of the sarcomere. While the constituent components of the sarcomere are well characterized, it is less clear how the activity and turnover of sarcomeric proteins is regulated. In particular, phosphorylation is critical regulator of muscle function. Thus, identification of regulatory kinases is key to understanding the sarcomere function. Pathogenic variants in alpha kinase 3 (ALPK3) cause cardiomyopathy and musculoskeletal disease, but little is known about this atypical kinase. Here we show that ALPK3 localizes to the M-Band of the sarcomere and define the ALPK3-dependent phosphoproteome. ALPK3 deficiency disrupted sarcomeric organization and calcium kinetics in hPSC-derived cardiomyocytes and reduced force generation in cardiac organoids. Phosphoproteomic profiling identified ALPK3-dependant phospho-peptides that were enriched for sarcomeric components of the M-band and the ubiquitin-binding protein SQSTM1. Analysis of the ALPK3 interactome confirmed binding to M-band proteins including SQSTM1. Importantly, in hPSC-derived cardiomyocytes modeling ALPK3 deficiency and cardiomyopathic ALPK3 mutations, sarcomeric organization and M-band localization of SQSTM1 were abnormal. These data suggest ALPK3 has an integral role in maintaining sarcomere integrity and proteostasis in striated muscle. We propose this mechanism may underly disease pathogenesis in patients with ALPK3 variants.

ORGANISM(S): Homo sapiens

PROVIDER: GSE215304 | GEO | 2023/01/10

REPOSITORIES: GEO

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