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

• Published in: Nature cardiovascular research Vol. 2; no. 2; p. 159
• Main Authors: McNamara, James W, Parker, Benjamin L, Voges, Holly K, Mehdiabadi, Neda R, Bolk, Francesca, Ahmad, Feroz, Chung, Jin D, Charitakis, Natalie, Molendijk, Jeffrey, Zech, Antonia T L, Lal, Sean, Ramialison, Mirana, Karavendzas, Kathy, Pointer, Hayley L, Syrris, Petros, Lopes, Luis R, Elliott, Perry M, Lynch, Gordon S, Mills, Richard J, Hudson, James E, Watt, Kevin I, Porrello, Enzo R, Elliott, David A
• Format: Journal Article
• Language: English
• Published: England 01.02.2023
• ISSN: 2731-0590
• DOI: 10.1038/s44161-023-00219-9

Muscle contraction is driven by the molecular machinery of the sarcomere. As phosphorylation is a critical regulator of muscle function, the identification of regulatory kinases is important for understanding sarcomere biology. 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 is an essential component of the M-band of the sarcomere and define the ALPK3-dependent phosphoproteome. ALPK3 deficiency impaired contractility both in human cardiac organoids and in the hearts of mice harboring a pathogenic truncating Alpk3 variant. ALPK3-dependent phosphopeptides were enriched for sarcomeric components of the M-band and the ubiquitin-binding protein sequestosome-1 (SQSTM1) (also known as p62). Analysis of the ALPK3 interactome confirmed binding to M-band proteins including SQSTM1. In human pluripotent stem cell-derived cardiomyocytes modeling cardiomyopathic ALPK3 mutations, sarcomeric organization and M-band localization of SQSTM1 were abnormal suggesting that this mechanism may underly disease pathogenesis.