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.

中文翻译：

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POST1 / C12ORF49通过促进Site-1蛋白酶成熟来调节SREBP途径

甾醇调节元件结合蛋白（SREBPs）是脂质代谢的关键转录调节因子。SREBP的激活需要将SREBP前体从内质网转移到高尔基体，在高尔基体中先后被位点1蛋白酶（S1P）和位点2蛋白酶裂解，并释放核形式来调节基因表达。为了搜索调节胆固醇代谢的新基因，我们进行了全基因组CRISPR / Cas9敲除筛选，发现由C12ORF49编码的site-1蛋白酶（POST1）的伴侣与SREBP信号传导至关重要。消融POST1减少了核SREBP的生成并减少了SREBP目标基因的表达。POST1绑定S1P，它被合成为无活性的蛋白酶（A型），并通过涉及B'/ B和C'/ C的两步自催化过程完全成熟。POST1从S1P-B'/ B（规范裂解），特别是直接从S1P-A（非规范裂解）促进功能性S1P-C'/ C的产生。POST1介导的S1P激活对于其他S1P底物的切割也至关重要，这些底物包括ATF6，CREB3家族成员和N-乙酰氨基葡糖-1-磷酸转移酶的α/β亚基前体。在一起，我们证明POST1是控制S1P成熟的辅助因子，并在脂质稳态，未折叠的蛋白应答，脂蛋白代谢和溶酶体生物发生中起重要作用。也直接来自S1P-A（非规范性切割）。POST1介导的S1P激活对于其他S1P底物的切割也至关重要，这些底物包括ATF6，CREB3家族成员和N-乙酰氨基葡糖-1-磷酸转移酶的α/β亚基前体。在一起，我们证明POST1是控制S1P成熟的辅助因子，并在脂质稳态，未折叠的蛋白应答，脂蛋白代谢和溶酶体生物发生中起重要作用。也直接来自S1P-A（非规范性切割）。POST1介导的S1P激活对于其他S1P底物的切割也至关重要，这些底物包括ATF6，CREB3家族成员和N-乙酰氨基葡糖-1-磷酸转移酶的α/β亚基前体。在一起，我们证明POST1是控制S1P成熟的辅助因子，并在脂质稳态，未折叠的蛋白应答，脂蛋白代谢和溶酶体生物发生中起重要作用。