Cideb controls sterol‐regulated ER export of SREBP/SCAP by promoting cargo loading at ER exit sites

Lu Su; Linkang Zhou; Feng‐Jung Chen; Huiming Wang; Hui Qian; Yuanyuan Sheng; Yuangang Zhu; Hua Yu; Xinqi Gong; Li'e Cai; Xuerui Yang; Li Xu; Tong‐Jin Zhao; John Zhong Li; Xiaowei Chen; Peng Liu

Ayuda

Cideb controls sterol‐regulated ER export of SREBP/SCAP by promoting cargo loading at ER exit sites

Lu Su ^[1] ; Linkang Zhou ^[1] ; Feng‐Jung Chen ^[1] ; Huimin Wang ^[2] ; Hui Qian ^[1] ; Yuanyuan Sheng ^[1] ; Yuangang Zhu ^[2] ; Hua Yu ^[3] ; Xinqi Gong ^[4] ; Li'e Cai ^[5] ; Xuerui Yang ^[1] ; Li Xu ^[1] ; Tong‐Jin Zhao ^[6] ; John Zhong Li ^[5] ; Xiao‐Wei Chen ^[2] ; Peng Li ^[1]
1. [1] Tsinghua University
  
  Tsinghua University
  
  China
2. [2] Peking University
  
  Peking University
  
  China
3. [3] Zhejiang University
  
  Zhejiang University
  
  China
4. [4] Renmin University of China
  
  Renmin University of China
  
  China
5. [5] Nanjing Medical University
  
  Nanjing Medical University
  
  China
6. [6] Xiamen University
  
  Xiamen University
  
  China
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Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 38, Nº. 8, 2019
Idioma: inglés
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Resumen
- SREBPs are master regulators of lipid homeostasis and undergo sterol‐regulated export from ER to Golgi apparatus for processing and activation via COPII‐coated vesicles. While COPII recognizes SREBP through its escort protein SCAP, factor(s) specifically promoting SREBP/SCAP loading to the COPII machinery remains unknown. Here, we show that the ER/lipid droplet‐associated protein Cideb selectively promotes the loading of SREBP/SCAP into COPII vesicles. Sterol deprivation releases SCAP from Insig and enhances ER export of SREBP/SCAP by inducing SCAP‐Cideb interaction, thereby modulating sterol sensitivity. Moreover, Cideb binds to the guanine nucleotide exchange factor Sec12 to enrich SCAP/SREBP at ER exit sites, where assembling of COPII complex initiates. Loss of Cideb inhibits the cargo loading of SREBP/SCAP, reduces SREBP activation, and alleviates diet‐induced hepatic steatosis. Our data point to a linchpin role of Cideb in regulated ER export of SREBP and lipid homeostasis.