Cideb controls sterol-regulated ER export of SREBP/SCAP by promoting cargo loading at ER exit sites

SREBPs are master regulators of lipid homeostasis and undergo sterol-regulated export from ER to Golgi apparatus for processing and activation via COPII-coated vesicles. While COPII recognizes SREBP through its escort protein SCAP, factor(s) specifically promoting SREBP/SCAP loading to the COPII machinery remains unknown. Here, we show that the ER/lipid droplet-associated protein Cideb selectively promotes the loading of SREBP/SCAP into COPII vesicles. Sterol deprivation releases SCAP from Insig and enhances ER export of SREBP/SCAP by inducing SCAP-Cideb interaction, thereby modulating sterol sensitivity. Moreover, Cideb binds to the guanine nucleotide exchange factor Sec12 to enrich SCAP/SREBP at ER exit sites, where assembling of COPII complex initiates. Loss of Cideb inhibits the cargo loading of SREBP/SCAP, reduces SREBP activation, and alleviates diet-induced hepatic steatosis. Our data point to a linchpin role of Cideb in regulated ER export of SREBP and lipid homeostasis.

Source: EMBO Journal - April 14, 2019 Category: Molecular Biology Authors: Su, L., Zhou, L., Chen, F.-J., Wang, H., Qian, H., Sheng, Y., Zhu, Y., Yu, H., Gong, X., Cai, L., Yang, X., Xu, L., Zhao, T.-J., Li, J. Z., Chen, X.-W., Li, P. Tags: Membrane & Intracellular Transport, Metabolism Articles Source Type: research