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Insulin Enhances Posttranslational Processing of Nascent SREBP‐1c by Promoting its Phosphorylation and Association with COPII vesicles
Author(s) -
Yellaturu Chandrahasa Reddy,
Deng Xiong,
Cagen Lauren M,
Wilcox Henry,
Park Edwards A,
Raghow Rajendra,
Elam Marshall B
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.522.12
Subject(s) - sterol regulatory element binding protein , copii , microbiology and biotechnology , endoplasmic reticulum , phosphorylation , grb10 , protein kinase a , golgi apparatus , biology , insulin receptor , biochemistry , chemistry , insulin , transcription factor , secretory pathway , endocrinology , insulin resistance , gene
The regulation of lipid homeostasis by insulin is mediated in part by the enhanced transcription of the gene encoding the sterol regulatory element‐binding protein‐1c (SREBP‐1c). Nascent SREBP‐1c is synthesized and embedded in the endoplasmic reticulum (ER) and must be transported to the Golgi in coatomer protein II (COPII) vesicles where two sequential cleavages generate the transcriptionally active N‐terminal fragment, nSREBP‐1c. There is limited indirect evidence to suggest that insulin may also regulate the posttranslational processing of the nascent SREBP‐1c protein. Therefore, we designed experiments to directly assess the action of insulin on the posttranslational processing of epitope‐tagged full‐length SREBP‐1c and SREBP‐2 proteins expressed in cultured hepatocytes. We demonstrate that insulin treatment led to enhanced phosphorylation of ER‐bound nascent SREBP‐1c protein that was associated with increased affinity of the SREBP‐1c cleavage‐activating protein (SCAP)/SREBP‐1c complex for the Sec23/24 proteins of the COPII vesicles. Furthermore, chemical and molecular inhibitors of the phosphoinositide 3‐kinase (PI3‐kinase) pathway and its downstream kinase PKB prevented both insulin‐mediated enhanced phosphorylation of the nascent SREBP‐1c protein and its posttranslational processing. Insulin had no effect on the proteolysis of the nascent SREBP‐2 under identical conditions. Thus, insulin selectively stimulates the processing of SREBP‐1c in rat hepatocytes by enhancing the association between the SCAP/SREBP‐1c complex and COPII proteins. The effect of insulin is tightly linked to PI3‐kinase and PKB‐dependent serine phosphorylation of the precursor SREBP‐1c protein.