Human leukocyte antigen F-associated transcript 10 regulates the I Ks potassium channel by competing for Kv7.1 ubiquitination.

The protein expression and function changes from the slow-delayed rectifying current, , are tightly associated with ventricular cardiac arrhythmias. Human leukocyte antigen F-associated transcript 10 (FAT10), a member of the ubiquitin-like-modifier family, exerts a protective effect against myocardial ischaemia. However, whether or how FAT10 influences the function of remains unclear. Here, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and knockout HEK293 () cells through CRISPR-Cas9 technology were used to evaluate the novel modulation of FAT10 in function. Patch-clamp studies showed that the overexpression of FAT10 significantly enhanced the current density of both in hiPSC-CMs and HEK293- cells. In addition, a shortened action potential duration (APD) was seen from hiPSC-CMs transfected with the virus. Then, a series of molecular approaches from neonatal rat cardiomyocytes, H9C2 cells and HEK293 cells were used to determine the regulatory mechanism of FAT10 in . First, western blot assays indicated that the expression of Kv7.1, the alpha-subunit of , was increased when FAT10 was overexpressed. Furthermore, immunofluorescence and co-immunoprecipitation assays demonstrated that FAT10 could interact with Kv7.1. Notably, FAT10 impedes Kv7.1 ubiquitination and degradation, thereby stabilizing its expression. Finally, a hypoxia model of hiPSC-CMs was established, and the overexpression of FAT10 showed a protective effect against hypoxia-induced decreases in the current density of . Taken together, these findings revealed a novel role of FAT10 in the regulation of the potassium channel by competing for Kv7.1 ubiquitination, which provides a new electrophysiological insight that FAT10 could modulate Kv7.1. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.