UC San Diego

Alpha Protein Kinase 3 (ALPK3) is an alpha kinase highly expressed in skeletal and cardiac muscles. Recent studies reveal that the biallelic truncating mutations in ALPK3 are associated with pediatric cardiomyopathy in human patients, suggesting that ALPK3 plays an essential role in cardiac development and function. However, no in vivo studies have elucidated the cardiac function of ALPK3; the subcellular localization of ALPK3 in cardiomyocyte is unknown, and whether the putative kinase activity is essential for the function of ALPK3 remains to be investigated. Utilizing ALPK3 global and cardiac specific knock out mouse models, we show that both the global and cardiac specific loss of ALPK3 leads to progressive dilated cardiomyopathy and premature lethality in mice. To investigate whether the putative kinase activity of ALPK3 is essential for its cardiac function, we mutate the invariant catalytic lysine residue in the alpha kinase domain of ALPK3 in mice and show that mice harboring the homozygous lysine mutation do not develop cardiac defects. Our in vitro and in vivo data further indicate that ALPK3 localizes in the nucleus of cardiomyocyte. In summary, our present study suggests that ALPK3 is a nucleus-localized protein indispensable for cardiac development and function, and that ALPK3 functions by protein-protein interactions independently of its putative kinase activity in heart.