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

Protein Cell. 2021 Apr;12(4):279-296. doi: 10.1007/s13238-020-00753-3. Epub 2020 Jul 14.

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; activating transcription factor 6; mannose-6-phosphate; proteolytic activation; site-1 protease; unfolded protein response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CRISPR-Cas Systems
  • HeLa Cells
  • Humans
  • Lipoproteins / biosynthesis
  • Lipoproteins / genetics
  • Lysosomes / genetics
  • Lysosomes / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Signal Transduction*
  • Sterol Regulatory Element Binding Proteins / genetics
  • Sterol Regulatory Element Binding Proteins / metabolism*

Substances

  • Lipoproteins
  • Membrane Proteins
  • SPRING1 protein, human
  • Sterol Regulatory Element Binding Proteins