Insulin-induced de novo lipid synthesis occurs mainly via mTOR-dependent regulation of proteostasis of SREBP-1c
| Autor: | Robert N. O'Meally, Gipsy Majumdar, Marshall B. Elam, Robert N. Cole, Rajendra Raghow, Qingming Dong |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Transcription Genetic Clinical Biochemistry Serine 03 medical and health sciences Transactivation symbols.namesake 0302 clinical medicine Cell Line Tumor Humans Molecular Biology Chemistry Kinase Endoplasmic reticulum Lipogenesis TOR Serine-Threonine Kinases Ribosomal Protein S6 Kinases 70-kDa Cell Biology General Medicine Golgi apparatus Lipids Cell biology 030104 developmental biology Proteostasis 030220 oncology & carcinogenesis symbols Hepatocytes Phosphorylation Sterol Regulatory Element Binding Protein 1 |
| Zdroj: | Molecular and cellular biochemistry. 463(1-2) |
| ISSN: | 1573-4919 |
| Popis: | Insulin stimulates de novo lipid synthesis in the liver and in cultured hepatocytes via its ability to activate sterol regulatory element-binding protein 1c (SREBP-1c). Although PI3K-AKT-mTORC1-p70S6K-signaling kinases are known to drive feed-forward expression of SREBP-1c, the identity of the phosphorylated amino acid residue(s) putatively involved in insulin-stimulated de novo lipogenesis remains elusive. We obtained in silico and mass spectrometry evidence, that was combined with siRNA strategies, to discover that insulin-induced phosphorylation of serine 418, serine 419, and serine 422 in rat SREBP-1c was most likely mediated by p70S6 kinase. Here, for the first time, we show that insulin-induced phosphorylation of these 3 serine residues mainly impinged on the mechanisms of proteostasis of both full-length and mature SREBP-1c in the McArdle-RH7777 hepatoma cells. Consistent with this conclusion, nascent SREBP-1c, substituted with phosphomimetic aspartic acid residues at these 3 sites, was resistant to proteasomal degradation. As a consequence, endoplasmic reticulum to Golgi migration and proteolytic maturation of pSREBP-1c was significantly enhanced which led to increased accumulation of mature nSREBP-1c, even in the absence of insulin. Remarkably, aspartic acid substitutions at S418, S419 and S422 also protected the nascent SREBP-1c from ubiquitin-mediated proteasome degradation thus increasing its steady-state levels and transactivation potential in the nucleus. These complementary effects of p70S6K-mediated phosphorylation on proteostasis of pSREBP-1c were necessary and sufficient to account for insulin's ability to enhance transcription of genes controlling de novo lipogenesis in hepatocytes. |
| Databáze: | OpenAIRE |
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