Journal Article

POST1/C12ORF49 regulates the SREBP pathway by promoting site-1 protease maturation

Shi, Xiong-Jie, Song, Bao-Liang, Luo, Jie, Wang, Ju-Qiong, Zhou, Zi-Mu, Xiao, Jian, Xiong, Yanni, Dong, Le-Wei, Yang, Liu-Ting, Zhao, Xiaolu

2021

Overview

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.

• Publisher: Higher Education Press,Springer Nature B.V,Oxford University Press
• Subject: activating transcription factor 6 / Biochemistry / Biomedical and Life Sciences / Cell Biology / Cholesterol / CRISPR / Developmental Biology / Endoplasmic reticulum / Gene expression / Genomes / Golgi apparatus / Homeostasis / Human Genetics / Life Sciences / Lipid metabolism / mannose-6-phosphate / Metabolism / N-Acetylglucosamine / Phosphotransferase / Protein folding / Protein Science / Protein turnover / Proteinase / proteolytic activation / Regulatory sequences / Research Article / site-1 protease / SREBP / Stem Cells / Sterol regulatory element-binding protein / Transcription / unfolded protein response