PGRMC2 is an intracellular haem chaperone critical for adipocyte function
PGRMC2 is an intracellular haem chaperone critical for adipocyte function
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DOI：
10.1038/s41586-019-1774-2
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发表时间：
2019-12-05
期刊：
影响因子：
64.8
通讯作者：
Saez, Enrique
中科院分区：
文献类型：
--
作者：
Galmozzi, Andrea;Kok, Bernard P.;Saez, Enrique
血红素是许多蛋白质的重要辅基，也是许多生理过程中的中心信号分子（1，2）。血红素的化学反应性意味着需要细胞内伴侣蛋白网络来避免游离血红素的细胞毒性作用，但这种运输途径的成分尚不清楚（3，4）。血红素的合成在线粒体中完成，铁螯合酶将铁加入原卟啉IX中。这种重要但高度反应性的代谢物如何从线粒体传递到整个细胞中的血蛋白仍然不清楚（3，4）。在这里，我们表明，孕激素受体膜组件2（PGRMC 2）是需要交付的不稳定，或信号血红素，到细胞核。棕色脂肪中PGMRC 2的缺失，对血红素有很高的需求，减少了细胞核中的不稳定血红素，增加了血液反应转录抑制因子Rev-Erb α和BACH 1的稳定性。随后基因表达的改变导致严重的线粒体缺陷，使得脂肪特异性PGRMC 2缺失小鼠无法激活适应性产热，并且在喂食高脂肪饮食时易于发生更大的代谢恶化。相比之下，用小分子PGRMC 2激活剂治疗的肥胖糖尿病小鼠显示出糖尿病特征的显着改善。这些研究揭示了PGRMC 2在细胞内血红素转运中的作用，揭示了脂肪组织血红素动力学对生理学的影响，并表明PGRMC 2的调节可能逆转脂肪细胞中与肥胖相关的缺陷。
Haem is an essential prosthetic group of numerous proteins and a central signalling molecule in many physiologic processes(1,2). The chemical reactivity of haem means that a network of intracellular chaperone proteins is required to avert the cytotoxic effects of free haem, but the constituents of such trafficking pathways are unknown(3,4). Haem synthesis is completed in mitochondria, with ferrochelatase adding iron to protoporphyrin IX. How this vital but highly reactive metabolite is delivered from mitochondria to haemoproteins throughout the cell remains poorly defined(3,4). Here we show that progesterone receptor membrane component 2 (PGRMC2) is required for delivery of labile, or signalling haem, to the nucleus. Deletion of PGMRC2 in brown fat, which has a high demand for haem, reduced labile haem in the nucleus and increased stability of the haem-responsive transcriptional repressors Rev-Erb alpha and BACH1. Ensuing alterations in gene expression caused severe mitochondrial defects that rendered adipose-specific PGRMC2-null mice unable to activate adaptive thermogenesis and prone to greater metabolic deterioration when fed a high-fat diet. By contrast, obese-diabetic mice treated with a small-molecule PGRMC2 activator showed substantial improvement of diabetic features. These studies uncover a role for PGRMC2 in intracellular haem transport, reveal the influence of adipose tissue haem dynamics on physiology and suggest that modulation of PGRMC2 may revert obesity-linked defects in adipocytes.