Abstract

Ribonuclease (RNase) III Drosha initiates microRNA (miRNA) biogenesis. Emerging evidence suggests that Drosha modulates processes beyond miRNA biogenesis, indicative of the functional complexity of Drosha. Here, we show that Drosha facilitates activation of sterol regulatory element-binding protein 1 (SREBP1), the central player in triglyceride (TG) biosynthesis, in an RNase activity-independent manner. Mechanistically, cytoplasmic Drosha interacts with Sec31, a subunit of coat protein complex II (COPII), through its arginine/serine (RS)-rich domain. This interaction promotes COPII-mediated transport and activation of SREBP1. Moreover, Akt phosphorylates Drosha at Ser237 in the RS-rich domain, which is required for the Drosha-Sec31 interaction, SREBP1 processing, and TG accumulation in response to insulin. The Akt-Drosha-SREBP1 axis was hyperactivated in mice fed a high-fat, high-sugar diet, and hepatic Drosha deletion or administration of an interfering peptide that blocked Akt-mediated phosphorylation of Drosha ameliorated liver TG deposition and insulin resistance in this mouse model. Thus, our findings uncover a noncanonical function of Drosha involved in SREBP1 processing and lipogenesis.