Cideb controls sterol-regulated ER export of SREBP/SCAP by promoting cargo loading at ER exit sites.,The EMBO Journal

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Cideb controls sterol-regulated ER export of SREBP/SCAP by promoting cargo loading at ER exit sites.
The EMBO Journal ( IF 9.4 ) Pub Date : 2019-03-11 , DOI: 10.15252/embj.2018100156
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,

6} , Xuerui Yang ₇ , Li Xu ₁ , Tong-Jin Zhao ₈ , John Zhong Li _{5,

6} , Xiao-Wei Chen ₉ , Peng Li ₁₀

Affiliation

State Key Laboratory of Membrane Biology and Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
State Key Laboratory of Membrane Biology, Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China.
The First Affiliated Hospital and Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, School of Medicine, Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.
Mathematical Intelligence Application Lab, Institute for Mathematical Sciences, Renmin University of China, Beijing, China.
Key Laboratory of Rare Metabolic Disease, The Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Molecular Biology and Biochemistry, Nanjing Medical University, Nanjing, Jiangsu, China.
MOE Key Laboratory of Bioinformatics, Center for Synthetic & Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China.
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
State Key Laboratory of Membrane Biology, Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China
State Key Laboratory of Membrane Biology and Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China

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.

中文翻译：

Cideb通过促进ER出口处的货物装载来控制固醇调节的SREBP / SCAP的ER出口。

SREBPs是脂质稳态的主要调节剂，并通过ER进行固醇调节出口到高尔基体，以通过COPII涂层的囊泡进行加工和活化。尽管COPII通过其伴游蛋白SCAP识别SREBP，但尚不清楚特异性促进SREBP / SCAP加载至COPII机制的因子。在这里，我们表明，ER /脂质液滴相关蛋白Cideb选择性地促进SREBP / SCAP加载到COPII囊泡中。甾醇剥夺通过诱导SCAP-Cideb相互作用从Insig释放SCAP，并增强SREBP / SCAP的ER出口，从而调节固醇敏感性。此外，Cideb与鸟嘌呤核苷酸交换因子Sec12结合，以在ER出口位点富集SCAP / SREBP，在那里COPII复合物开始组装。Cideb的损失会抑制SREBP / SCAP的货物装载，降低SREBP激活，并减轻饮食引起的肝脂肪变性。我们的数据表明，Cideb在调节SREBP的ER出口和脂质体内平衡中起关键作用。

更新日期：2019-04-15

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