STARD1 Functions in Mitochondrial Cholesterol Metabolism and Nascent HDL Formation. Gene Expression and Molecular mRNA Imaging Show Novel Splicing and a 1:1 Mitochondrial Association.
STARD1 Functions in Mitochondrial Cholesterol Metabolism and Nascent HDL Formation. Gene Expression and Molecular mRNA Imaging Show Novel Splicing and a 1:1 Mitochondrial Association.
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DOI：
10.3389/fendo.2020.559674
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发表时间：
2020
影响因子：
5.2
通讯作者：
Jefcoate CR
中科院分区：
文献类型：
--
作者：
Larsen MC;Lee J;Jorgensen JS;Jefcoate CR
STARD 1在类固醇生成细胞中将胆固醇（CHOL）从线粒体外膜（OMM）移动到内膜（IMM）。该活性被整合到CHOL运输和合成稳态中，涉及通过SR-B1和LDL受体的摄取以及通过内体、ER和脂滴的分布。在肾上腺细胞中，STARD 1被输入线粒体基质，伴随着数百个CHOL分子的递送。这种转移限制了CYP 11 A1介导的双烯醇酮的产生。CHOL转移与OMM处STARD 1 mRNA的翻译偶联。在睾丸细胞中，较慢的CHOL运输似乎是有限的。STARD 1还通过ER OMM触点在较慢的过程中发挥作用。STARD 1的START结构域被一个基因家族利用，该基因家族包括转移CHOL的另外的STARD（形式3-6）和GRAMD 1B蛋白。STARD形式2和7递送磷脂酰胆碱。STARD 1和STARD 7通过超过50个氨基酸的N-末端结构域（NTD）将其各自的活性靶向线粒体。NTD对类固醇生成不是必需的，但具有组织选择性增强作用（睾丸>>肾上腺）。由线粒体加工蛋白酶（MPP）切割的三个保守位点产生三种形式，每种形式都可能具有特定的功能，如STARD 7所示。STARD 1在巨噬细胞和心脏修复成纤维细胞中表达。其他功能包括通过CYP 27 A1代谢CHOL，其指导LXR和CHOL输出过程的激活。STARD 1从交替的多聚腺苷酸化产生3.5-和1.6-kb mRNA。3.5 kb的形式专门结合PKA诱导的调节因子TIS 11b，TIS 11b结合在延伸的3 'UTR中的保守位点以控制mRNA翻译和周转。STARD 1表达还表现出一种新的、缓慢的剪接，其延迟了mRNA向线粒体的剪接递送。PKA对转录的刺激通过抑制激活CRTC/CREB/CBP启动子复合物的SIK形式来指导。这一过程对体内脉冲性激素激活至关重要。sm-FISH RNA成像显示单个STARD 1 mRNA颗粒从基因位点处初级转录物的不对称积累流向具有核周线粒体的3.5-kb mRNA的1：1复合物。肾上腺细胞与睾丸细胞相似，但在激素激活前可明显表达基础蛋白。这种差异在培养和体内是保守的。
STARD1 moves cholesterol (CHOL) from the outer mitochondrial membrane (OMM) to the inner membrane (IMM) in steroidogenic cells. This activity is integrated into CHOL trafficking and synthesis homeostasis, involving uptake through SR-B1 and LDL receptors and distribution through endosomes, ER, and lipid droplets. In adrenal cells, STARD1 is imported into the mitochondrial matrix accompanied by delivery of several hundred CHOL molecules. This transfer limits CYP11A1-mediated generation of pregnenolone. CHOL transfer is coupled to translation of STARD1 mRNA at the OMM. In testis cells, slower CHOL trafficking seems to be limiting. STARD1 also functions in a slower process through ER OMM contacts. The START domain of STARD1 is utilized by a family of genes, which includes additional STARD (forms 3–6) and GRAMD1B proteins that transfer CHOL. STARD forms 2 and 7 deliver phosphatidylcholine. STARD1 and STARD7 target their respective activities to mitochondria, via N-terminal domains (NTD) of over 50 amino acids. The NTD is not essential for steroidogenesis but exerts tissue-selective enhancement (testis>>adrenal). Three conserved sites for cleavage by the mitochondrial processing protease (MPP) generate three forms, each potentially with specific functions, as demonstrated in STARD7. STARD1 is expressed in macrophage and cardiac repair fibroblasts. Additional functions include CHOL metabolism by CYP27A1 that directs activation of LXR and CHOL export processes. STARD1 generates 3.5- and 1.6-kb mRNA from alternative polyadenylation. The 3.5-kb form exclusively binds the PKA-induced regulator, TIS11b, which binds at conserved sites in the extended 3’UTR to control mRNA translation and turnover. STARD1 expression also exhibits a novel, slow splicing that delayed splicing delivery of mRNA to mitochondria. Stimulation of transcription by PKA is directed by suppression of SIK forms that activate a CRTC/CREB/CBP promoter complex. This process is critical to pulsatile hormonal activation in vivo. sm-FISH RNA imaging shows a flow of single STARD1 mRNA particles from asymmetric accumulations of primary transcripts at gene loci to 1:1 complex of 3.5-kb mRNA with peri-nuclear mitochondria. Adrenal cells are similar but distinguished from testis cells by appreciable basal expression prior to hormonal activation. This difference is conserved in culture and in vivo.
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影响因子：
32.4
作者：
Blanc M;Hsieh WY;Robertson KA;Kropp KA;Forster T;Shui G;Lacaze P;Watterson S;Griffiths SJ;Spann NJ;Meljon A;Talbot S;Krishnan K;Covey DF;Wenk MR;Craigon M;Ruzsics Z;Haas J;Angulo A;Griffiths WJ;Glass CK;Wang Y;Ghazal P
通讯作者：
Ghazal P
影响因子：
13.3
作者：
Dai S;Dulcey AE;Hu X;Wassif CA;Porter FD;Austin CP;Ory DS;Marugan J;Zheng W
通讯作者：
Zheng W
DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1126/science.aag1417
发表时间：
2017-03-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Castellano BM;Thelen AM;Moldavski O;Feltes M;van der Welle RE;Mydock-McGrane L;Jiang X;van Eijkeren RJ;Davis OB;Louie SM;Perera RM;Covey DF;Nomura DK;Ory DS;Zoncu R
通讯作者：
Zoncu R
影响因子：
4.1
作者：
Castillo, Ana F.;Orlando, Ulises;Podesta, Ernesto J.
通讯作者：
Podesta, Ernesto J.