Why the study?
Pathogenic variants in ALPK3 cause cardiomyopathy and musculoskeletal disease, but how ALPK3 mutations lead to disease remains unclear because little is known about this atypical kinase.
ALPK3 localizes to the M-band and its deficiency disrupts sarcomere integrity and proteostasis, providing a mechanistic basis for ALPK3-related cardiomyopathy.
SUMMARY Pathogenic variants in alpha kinase 3 ( ALPK3 ) cause cardiomyopathy and musculoskeletal disease. How ALPK3 mutations result in disease remains unclear because little is known about this atypical kinase. Using a suite of engineered human pluripotent stem cells (hPSCs) we show that ALPK3 localizes to the M-Band of the sarcomere. 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 ofSQSTM1 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.
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McNamara et al. (2022) studied Cardiomyopathy and musculoskeletal disease associated with ALPK3 variants. ALPK3 deficiency and cardiomyopathic ALPK3 mutations was evaluated on Sarcomeric organization, calcium kinetics, and force generation.
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