Cytoskeletal remodeling and enhanced autophagy drive an adaptive response to loss of Calsequestrin in a model of inherited arrhythmias

Abstract

Calcium transients between the Sarcoplasmic Reticulum (SR) and the cytoplasm are essential for coordinated contraction in cardiomyocytes. Loss of the SR protein Calsequestrin 2 (CASQ2) causes the recessive form of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT2) by increasing the diastolic opening probability of the main SR calcium channel Ryanodine receptor 2 (RyR2), and by causing an unexplained decrease of its regulatory protein Triadin (TRDN). Here we studied the mechanisms of TRDN reduction in CASQ2-KO mice and show that ablation of CASQ2 activates histone-deacetylase HDAC6, which regulates several cellular processes. In CASQ2 deficient cardiomyocytes, HDAC6 reduces alpha-Tubulin acetylation, thus impairing microtubule stability and altering TRDN trafficking and co-localization with RyR2. Misplaced TRDN binds HSP70, forming Aggresomes that are degraded by autophagy. The study identifies a novel cascade of post-transcriptional events initiated by the loss of CASQ2 that leads to a major rearrangement of SR protein trafficking and stability in cardiomyocytes