Suppression of SREBP by a transmembrane protein mutated in cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder characterized by the replacement of myocardial tissue with adipose tissue. One of the frequently mutated proteins in ARVC is TMEM43, which encodes a transmembrane protein primarily localized to the endoplasmic reticulum (ER) and nuclear membranes and stabilized by interacting with squalene synthase (SQS). However, its precise role in ARVC pathogenesis remains unclear. The present study demonstrates that TMEM43 suppresses the expression of SQS and other lipogenic proteins by inhibiting sterol regulatory element-binding proteins (SREBPs). Mechanistic analysis revealed that TMEM43 inhibits nuclear SREBP activity by binding to LRPPRC, which serves as a transcriptional coactivator for SREBP in coordination with PGC1β. TMEM43 sequesters LRPPRC to the nuclear membrane, disrupting its coactivator function and inhibiting SREBP activity. Given the role of SREBPs in adipogenesis, our findings highlight TMEM43 as a key regulator of adipocyte versus cardiomyocyte differentiation.