HRG-9 homologues regulate haem trafficking from haem-enriched compartments.
HRG-9 homologues regulate haem trafficking from haem-enriched compartments.
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HRG-9 同源物调节来自富含血红素区室的血红素运输
DOI：
10.1038/s41586-022-05347-z
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发表时间：
2022-10
期刊：
影响因子：
64.8
通讯作者：
Chen, Caiyong
中科院分区：
文献类型：
--
作者：
Sun, Fengxiu;Zhao, Zhenzhen;Willoughby, Mathilda M.;Shen, Shuaiqi;Zhou, Yu;Shao, Yiyan;Kang, Jing;Chen, Yongtian;Chen, Mengying;Yuan, Xiaojing;Hamza, Iqbal;Reddi, Amit R.;Chen, Caiyong
血红素是一种含铁的四吡咯，对多种细胞和生理过程至关重要。血红素结合蛋白存在于几乎所有的细胞区室中，但是调节血红素在细胞内的运输和使用的分子机制仍然知之甚少。在这里，我们表明，血红素反应基因9（HRG-9）（也被称为运输和高尔基体组织2（TANGO 2））是一个进化上保守的血红素分子伴侣，在运输血红素的血红素存储或合成位点在真核细胞中的关键作用。秀丽隐杆线虫hrg-9和其parabolishrg-10的缺失导致血红素在溶酶体相关细胞器中的积累，溶酶体相关细胞器是蠕虫中的血红素储存位点。类似地，在酵母和哺乳动物细胞中hrg-9同源物TANGO 2的缺失诱导血红素合成位点线粒体中的血红素过载。我们证明，TANGO 2结合血红素和转移它从细胞膜的apo-haemoproteins。值得注意的是，纯合子tango 2 −/−斑马鱼幼鱼会出现多种症状，包括脑病、心律失常和肌病，并在早期发育过程中死亡。这些缺陷部分类似于人类TANGO 2相关代谢性脑病和心律失常的症状，这是一种由TANGO 2突变引起的遗传性疾病。因此，HRG-9作为细胞内血红素分子伴侣的鉴定为探索TANGO 2相关疾病的病因学和治疗提供了生物学基础。
Haem is an iron-containing tetrapyrrole that is critical for a variety of cellular and physiological processes. Haem binding proteins are present in almost all cellular compartments, but the molecular mechanisms that regulate the transport and use of haem within the cell remain poorly understood. Here we show that haem-responsive gene 9 (HRG-9) (also known as transport and Golgi organization 2 (TANGO2)) is an evolutionarily conserved haem chaperone with a crucial role in trafficking haem out of haem storage or synthesis sites in eukaryotic cells. Loss of Caenorhabditis elegans hrg-9 and its paralogue hrg-10 results in the accumulation of haem in lysosome-related organelles, the haem storage site in worms. Similarly, deletion of the hrg-9 homologue TANGO2 in yeast and mammalian cells induces haem overload in mitochondria, the site of haem synthesis. We demonstrate that TANGO2 binds haem and transfers it from cellular membranes to apo-haemoproteins. Notably, homozygous tango2−/− zebrafish larvae develop pleiotropic symptoms including encephalopathy, cardiac arrhythmia and myopathy, and die during early development. These defects partially resemble the symptoms of human TANGO2-related metabolic encephalopathy and arrhythmias, a hereditary disease caused by mutations in TANGO2. Thus, the identification of HRG-9 as an intracellular haem chaperone provides a biological basis for exploring the aetiology and treatment of TANGO2-related disorders.
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DOI：
10.1016/0006-291x(79)91133-1
发表时间：
1979-01-01
影响因子：
3.1
作者：
EBERT, PS;HESS, RA;TSCHUDY, DP
通讯作者：
TSCHUDY, DP
影响因子：
64.8
作者：
Galmozzi, Andrea;Kok, Bernard P.;Saez, Enrique
通讯作者：
Saez, Enrique
影响因子：
64.8
作者：
Bard, F;Casano, L;Malhotra, V
通讯作者：
Malhotra, V
影响因子：
9.8
作者：
Kremer, Laura S.;Distelmaier, Felix;Haack, Tobias B.
通讯作者：
Haack, Tobias B.
影响因子：
2.7
作者：
Ganis JJ;Hsia N;Trompouki E;de Jong JL;DiBiase A;Lambert JS;Jia Z;Sabo PJ;Weaver M;Sandstrom R;Stamatoyannopoulos JA;Zhou Y;Zon LI
通讯作者：
Zon LI