@article{5515fe27c1e84eceb84acfa694622fdb,
title = "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. 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.",
author = "McNamara, {James W.} and Parker, {Benjamin L.} and Voges, {Holly K.} and Mehdiabadi, {Neda R.} and Francesca Bolk and Feroz Ahmad and Chung, {Jin D.} and Natalie Charitakis and Jeffrey Molendijk and Zech, {Antonia T.L.} and Sean Lal and Mirana Ramialison and Kathy Karavendzas and Pointer, {Hayley L.} and Petros Syrris and Lopes, {Luis R.} and Elliott, {Perry M.} and Lynch, {Gordon S.} and Mills, {Richard J.} and Hudson, {James E.} and Watt, {Kevin I.} and Porrello, {Enzo R.} and Elliott, {David A.}",
note = "Funding Information: We thank the National Health and Medical Research Council of Australia (E.R.P., D.A.E., B.L.P.; grant nos. GNT2008376, 1160256 and 1160257), the Australian Research Council (E.R.P.; grant no. DP190101972), the Heart Foundation of Australia (E.R.P., D.A.E.; grant nos. 104997 and 105146), the Medical Research Future Fund (E.R.P., D.A.E.; grant nos. MRF2007316 and MRF2007471), the Stafford Fox Medical Research Foundation (E.R.P.), the Australian Genomics Health Alliance (J.W.M., E.R.P., D.A.E.), the Royal Children{\textquoteright}s Hospital Foundation (E.R.P.) and the Murdoch Children{\textquoteright}s Research Institute (MCRI) Early Career Researcher Award (J.W.M.) for grant and fellowship support. The MCRI is supported by the Victorian Government{\textquoteright}s Operational Infrastructure Support Program. E.R.P. and D.A.E. are principal investigators of the Novo Nordisk Foundation Center for Stem Cell Medicine, which is supported by Novo Nordisk Foundation grant no. NNF21CC0073729. L.R.L. is supported by a UK Research and Innovation Medical Research Council clinical academic research partnership award (no. MR/T005181/1). The generation of the Alpk3 mice used in this study was supported by Phenomics Australia and the Australian Government through the National Collaborative Research Infrastructure Strategy program. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. W1538X Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = feb,
doi = "10.1038/s44161-023-00219-9",
language = "English",
volume = "2",
pages = "159--173",
journal = "Nature Cardiovascular Research",
issn = "2731-0590",
publisher = "Nature Publishing Group",
number = "2",
}
