title: A novel processing system of sterol regulatory element-binding protein-1c regulated by polyunsaturated fatty acid.
abstract: The proteolytic cascade is the key step in transactivation of sterol regulatory element-binding proteins (SREBPs), a transcriptional factor of lipid synthesis. Proteolysis of SREBP-2 is strictly regulated by sterols, but that of SREBP-1c was not strongly sterol-regulated, but inhibited by polyunsaturated fatty acids (PUFAs). In this study, the proteolytic processing of SREBP-1 and -2 was examined by transfection studies of cDNA-encoding mutants in which all the known cleavage sites were disrupted. In cultured cells, sterol-regulated SREBP-2 processing was completely eliminated by mutation of cleavage sites. In contrast, the corresponding SREBP-1c mutants as well as wild type exhibited large amounts of cleaved products in the nuclear extracts from culture cells and murine liver in vivo. The nuclear form of the mutant SREBP-1c was induced by delipidated condition and suppressed by eicosapentaenoic acid, an n-3 PUFA, but not by sterols. This novel processing mechanism was affected by neither SREBP cleavage-activating protein (SCAP) nor insulin-induced gene (Insig)-1, unlike SREBP-2, but abolished by a serine protease inhibitor. Through analysis of deletion mutant, a site-2 protease recognition sequence (DRSR) was identified to be involved in this novel processing. These findings suggest that SREBP-1c cleavage could be subjected to a novel PUFA-regulated cleavage system in addition to the sterol-regulatory SCAP/Insig system.
authors.affiliation: Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., 722 Jimba-aza-Uenohara, Gotemba, Shizuoka 412-8524; and Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, Faculty of Medicine, and International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakakuki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawano
authors.forename: Tatsuto
authors.initials: T
authors.lastname: Notsu
authors.forename: Kazunori
authors.initials: K
authors.lastname: Imada
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mizuguchi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005231:Fatty Acids, Unsaturated / Q000378:metabolism* / Q000494:pharmacology; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D011499:Protein Processing, Post-Translational; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D013261:Sterols / Q000378:metabolism / Q000494:pharmacology
chemical_list: D005231:Fatty Acids, Unsaturated; C108626:INSIG1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497390:SREBF2 protein, human; C102196:SREBP cleavage-activating protein; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D013261:Sterols
keywords: SREBP; eicosapentaenoic acid; polyunsaturated fatty acids; processing; sterols