THOC4 regulates energy homeostasis by stabilizing TFEB mRNA during prolonged starvation

Abstract

TFEB, a bHLH transcription factor, is a master regulator of autophagy, lysosome biogenesis, and lipid catabolism. Compared to the post-translational regulation, the regulation of TFEB mRNA stability remains relatively uncharacterized. In this study, we identified the mRNA-binding protein THOC4 as a novel regulator of TFEB. In mammalian cells, siRNA-mediated knockdown of THOC4 decreased the level of TFEB protein to a greater extent than other bHLH transcription factors. THOC4 bound to TFEB mRNA and stabilized it after transcription through maintaining polyA length. We further found that this mode of regulation was conserved in C. elegans and was essential for TFEB mediated lipid break-down which becomes overrepresented during prolonged starvation. Taken together our study reveals the presence of an additional layer of TFEB regulation by THOC4 and provide novel insights into the function TFEB mediating autophagy and lipid metabolism.