Cytoplasmic RNase III Drosha controls lipogenesis by noncanonical regulation of SREBP1

RNase III Drosha initiates miRNA biogenesis. Emerging evidence suggests that Drosha modulate other processes beyond miRNA biogenesis, indicative of a functional complexity of Drosha. Here we show that Drosha facilitates activation of sterol regulatory element-binding protein 1 (SREBP1), the central player in triglycerides (TG) biosynthesis, in a RNase activity-independent manner. Mechanistically, cytoplasmic Drosha interacts with Sec31, a subunit of COPII, through its RS-rich domain. This interaction promotes COPII-mediated transportation of SREBP1 from endoplasmic reticulum to Golgi where it is proteolytically activated. Moreover, Akt phosphorylates Drosha at Ser237 in RS-rich domain, which is required for Drosha-Sec31 interaction, SREBP1 processing and TG accumulation in response to insulin. The Akt-Drosha-SREBP1 axis was hyperactivated in obese mice, and hepatic Drosha deletion or administration of an interfering peptide that blocked Akt-mediated phosphorylation of Drosha ameliorate liver TG deposition and insulin resistance. Thus, our findings uncover a noncanonical function of Drosha involved SREBP1 processing and lipogenesis.