Yanni Xiong
Liu-Ting Yang
Ju-Qiong Wang
Zi-Mu Zhou
Le-Wei Dong
Xiong-Jie Shi
Xiaolu Zhao
Jie Luo
Bao-Liang Song
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430072, China
Funds: We thank Ms. D. Liang and B.-Y. Xiang for technical assistance. This work was supported by grants from the National Natural Science Foundation of China (Grant Nos. 91954203, 31771568, 91754102 and 31690102), Ministry of Science and Technology of China (2016YFA0500100) and 111 Project of Ministry of Education of China (B16036). B.-L. Song acknowledges the support from the Tencent Foundation through the XPLORER PRIZE.
Received Date: 2020-04-12
Rev Recd Date:2020-06-17
Abstract
Abstract
Sterol-regulatory element binding proteins (SREBPs) are the key transcriptional regulators of lipid metabolism. The activation of SREBP requires translocation of the SREBP precursor from the endoplasmic reticulum to the Golgi, where it is sequentially cleaved by site-1 protease (S1P) and site-2 protease and releases a nuclear form to modulate gene expression. To search for new genes regulating cholesterol metabolism, we perform a genome-wide CRISPR/Cas9 knockout screen and find that partner of site-1 protease (POST1), encoded by C12ORF49, is critically involved in the SREBP signaling. Ablation of POST1 decreases the generation of nuclear SREBP and reduces the expression of SREBP target genes. POST1 binds S1P, which is synthesized as an inactive protease (form A) and becomes fully mature via a two-step autocatalytic process involving forms B'/B and C'/C. POST1 promotes the generation of the functional S1P-C'/C from S1P-B'/B (canonical cleavage) and, notably, from S1P-A directly (non-canonical cleavage) as well. This POST1-mediated S1P activation is also essential for the cleavages of other S1P substrates including ATF6, CREB3 family members and the α/β- subunit precursor of N-acetylglucosamine-1-phosphotransferase. Together, we demonstrate that POST1 is a cofactor controlling S1P maturation and plays important roles in lipid homeostasis, unfolded protein response, lipoprotein metabolism and lysosome biogenesis.Keywords: SREBP,
site-1 protease,
proteolytic activation,
unfolded protein response,
activating transcription factor 6,
mannose-6-phosphate
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