Scap-Insig-2-25HC复合物与细胞内胆固醇水平的调控

固醇调节原件结合蛋白(sterol regulatory element-binding protein,SREBP)是调节细胞内固醇类物质水平的重要细胞核转录因子,通过负反馈机制维持细胞内固醇稳态. SREBP裂解激活蛋白(SREBP-cleavage activating protein,Scap)和胰岛素诱导基因2 (insulin-induced gene-2,Insig-2)、25-羟基胆固醇(25-hydroxycholesterol,25HC)对SREBP激活、成熟及核转位具有重要调节作用.最近研究揭示了Scap-Insig-2-25HC复合物的分子结构,这对细胞内胆固醇代谢研究具有重要的意义.     

Deficiency of sterol regulatory element‐binding protein‐1c induces schizophrenia‐like behavior in mice

Schizophrenia is a hereditary disease that approximately 1% of the worldwide population develops. Many studies have investigated possible underlying genes related to schizophrenia. Recently, clinical studies suggested sterol regulatory element‐binding protein (SREBP) as a susceptibility gene in patients with schizophrenia. SREBP controls cellular lipid homeostasis by three isoforms: SREBP‐1a, SREBP‐1c and SREBP‐2. This study used SREBP‐1c knockout (KO) mice to examine whether a deficiency in SREBP‐1c would affect their emotional and psychiatric behaviors. Altered mRNA expression in genes downstream from SREBP‐1c was confirmed in the brains of SREBP‐1c KO mice. Schizophrenia‐like behavior, including hyperactivity during the dark phase, depressive‐like behavior, aggressive behavior and deficits in social interaction and prepulse inhibition, was observed in SREBP‐1c KO mice. Furthermore, increased volume of the lateral ventricle was detected in SREBP‐1c KO mice. The mRNA levels of several γ‐aminobutyric acid (GABA)‐receptor subtypes and/or glutamic acid decarboxylase 65/67 decreased in the hippocampus and medial prefrontal cortex of SREBP‐1c KO mice. Thus, SREBP‐1c deficiency may contribute to enlargement of the lateral ventricle and development of schizophrenia‐like behaviors and be associated with altered GABAergic transmission.     

Structure of the WD40 domain of SCAP from fission yeast reveals the molecular basis for SREBP recognition

The sterol regulatory element-binding protein (SREBP) and SREBP cleavage-activating protein (SCAP) are central players in the SREBP pathway, which control the cellular lipid homeostasis. SCAP binds to SREBP through their carboxyl (C) domains and escorts SREBP from the endoplasmic reticulum to the Golgi upon sterol depletion. A conserved pathway, with the homologues of SREBP and SCAP being Sre1 and Scp1, was identified in fission yeast Schizosaccharomyces pombe. Here we report the in vitro reconstitution of the complex between the C domains of Sre1 and Scp1 as well as the crystal structure of the WD40 domain of Scp1 at 2.1 Å resolution. The structure reveals an eight-bladed β-propeller that exhibits several distinctive features from a canonical WD40 repeat domain. Structural and biochemical characterization led to the identification of two Scp1 elements that are involved in Sre1 recognition, an Arg/Lys-enriched surface patch on the top face of the WD40 propeller and a 30-residue C-terminal tail. The structural and biochemical findings were corroborated by in vivo examinations. These studies serve as a framework for the mechanistic understanding and further functional characterization of the SREBP and SCAP proteins in fission yeast and higher organisms.     

Lanosterol metabolism and sterol regulatory element binding protein (SREBP) expression in male germ cell maturation

Expression of genes involved in cholesterol biosynthesis in male germ cells is insensitive to the negative cholesterol feedback regulation, in contrast to cholesterol level-sensitive/sterol regulatory element binding protein (SREBP)-dependent gene regulation in somatic cells. The role of sterol regulatory element binding proteins in spermatogenic cells was an enigma until recently, when a soluble, 55 kDa cholesterol-insensitive form of SREBP2 (SREBP2gc) was discovered [Mol. Cell. Endocrinol. 22 (2002) 8478], being translated from a germ cell-specific SREBP2 mRNA. Our RT-PCR results also show that SREBP2 as well as SREBP1c mRNAs are detectable in prepubertal and postpubertal male germ cells while SREBP1a is not detected. Surprisingly, three SREBP2 immunoreactive proteins (72, 63 and 55 kDa), that are not present in mouse liver nuclei, reside in testis nuclei of prepubertal and adult mice. The 55 kDa protein is likely SREBP2gc, the other two isoforms are novel. HPLC measurements in liver and testes of fasted prepubertal and postpubertal mice showed no significant difference in cholesterol level. However, FF-MAS and lanosterol/testis-meiosis activating sterol (T-MAS) intermediates that are detectable mainly in testes, increase in fasted postpubertal mice which coincides well with the elevated level of 68 kDa SREBP2. Similar to SREBP2gc, the two novel SREBP2 immunoreactive proteins seem to be insensitive to the level of cholesterol.     

肝细胞中活化转录因子ATF6抑制SREBP1的转录活性

内质网膜定位的活化转录因子ATF6和SREBP1均是经过蛋白酶切水解激活,激活后的ATF6(N)和SREBP1(N)进入细胞核内,分别指导内质网膜未折叠蛋白聚集反应相关基因和脂肪酸合成相关基因的表达.研究发现,肝细胞内葡萄糖饥饿激活ATF6并抑制SREBP1的转录活性及其靶基因的表达.过表达ATF6(N)能够抑制SREBP1介导的转录及其下游基因的表达.免疫共沉淀实验显示,ATF6(N)在细胞核内结合SREBP1(N),这种结合在无糖状况下增强.不同功能区缺失分析表明,ATF6和SREBP1通过亮氨酸拉链(leucinezipper)功能区相互作用.在葡萄糖饥饿状况下,ATF6对SREBP1转录活性的抑制保证了细胞基本生命活动所需要的能量.