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 通过促进位点 1 蛋白酶成熟来调节 SREBP 通路

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 SREBP 前体从内质网易位到高尔基体，在那里它被位点 1 蛋白酶 (S1P) 和位点 2 蛋白酶顺序切割并释放核形式以调节基因表达。为了寻找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 编码的位点 1 蛋白酶 (POST1) 的伙伴与 SREBP 信号传导密切相关。POST1 的消融减少了核 SREBP 的产生并降低了 SREBP 靶基因的表达。POST1 绑定 S1P，其合成为无活性蛋白酶（A 型），并通过涉及 B'/B 和 C'/C 型的两步自催化过程完全成熟。POST1 促进从 S1P-B'/B（规范切割），特别是直接从 S1P-A（非规范切割）生成功能性 S1P-C'/C。这种 POST1 介导的 S1P 激活对于切割其他 S1P 底物（包括 ATF6、CREB3 家族成员和 N-乙酰氨基葡萄糖-1-磷酸转移酶的 α/β-亚基前体）也是必不可少的。总之，我们证明 POST1 是控制 S1P 成熟的辅助因子，并在脂质稳态、未折叠蛋白反应、脂蛋白代谢和溶酶体生物发生中发挥重要作用。也直接来自 S1P-A（非规范裂解）。这种 POST1 介导的 S1P 激活对于切割其他 S1P 底物（包括 ATF6、CREB3 家族成员和 N-乙酰氨基葡萄糖-1-磷酸转移酶的 α/β-亚基前体）也是必不可少的。总之，我们证明 POST1 是控制 S1P 成熟的辅助因子，并在脂质稳态、未折叠蛋白反应、脂蛋白代谢和溶酶体生物发生中发挥重要作用。也直接来自 S1P-A（非规范裂解）。这种 POST1 介导的 S1P 激活对于切割其他 S1P 底物（包括 ATF6、CREB3 家族成员和 N-乙酰氨基葡萄糖-1-磷酸转移酶的 α/β-亚基前体）也是必不可少的。总之，我们证明 POST1 是控制 S1P 成熟的辅助因子，并在脂质稳态、未折叠蛋白反应、脂蛋白代谢和溶酶体生物发生中发挥重要作用。