期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 292, 期 7, 页码 3016-3028出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.767277
关键词
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资金
- JSPS KAKENHI [15H05781]
- Cross-ministerial Strategic Innovation Promotion Program [14533567]
- Japanese Agency for Medical Research and Development [16gm0910008h0001]
- Tojuro Iijima Foundation for Food Science and Technology
- Grants-in-Aid for Scientific Research [15H05781, 17F17100] Funding Source: KAKEN
Sterol regulatory element-binding proteins (SREBPs) are the key transcription factors that modulate lipid biosynthesis. SREBPs are synthesized as endoplasmic reticulum-bound precursors that require proteolytic activation in the Golgi apparatus. The stability and maturation of precursor SREBPs depend on their binding to SREBP cleavage-activating protein (SCAP), which escorts the SCAP-SREBP complex to the Golgi apparatus. In this study, we identified heat shock protein (HSP) 90 as a novel SREBP regulator that binds to and stabilizes SCAP-SREBP. In HepG2 cells, HSP90 inhibition led to proteasome-dependent degradation of SCAP-SREBP, which resulted in the down-regulation of SREBP target genes and the reduction in intracellular triglyceride and cholesterol levels. Wealso demonstrated in vivo that HSP90 inhibition decreased SCAP-SREBP protein, down-regulated SREBP target genes, and reduced lipids levels in mouse livers. We propose that HSP90 plays an indispensable role in SREBP regulation by stabilizing the SCAP-SREBP complex, facilitating the activation of SREBP to maintain lipids homeostasis.
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