美国斯克利普斯研究所Enrique Saez课题组发现，孕酮受体膜组分2（PGRMC2）是对脂肪细胞功能至关重要的细胞内血红素伴侣。相关论文11月20日在线发表在《自然》上。

研究人员发现孕酮受体膜组分2（PGRMC2），是游离的或信号通路中血红素传递到细胞核所必需的。在高需求血红素的棕色脂肪中，PGMRC2的缺失减少了细胞核中不稳定的血红素，并增加了血红素反应性转录抑制因子Rev-Erbα和BACH1的稳定性。

由此造成的基因表达改变造成了严重的线粒体缺陷，并导致脂肪组织特异性PGRMC2敲出的小鼠无法激活适应性产热功能，在食用高脂饮食时会造成更严重的代谢紊乱。相反，用小分子PGRMC2激活剂治疗的肥胖糖尿病小鼠显示出糖尿病特征的实质性改善。这些研究揭示了PGRMC2在细胞内血红素运输中的作用，以及脂肪组织血红素动力学对生理的影响，并表明对PGRMC2的调节可逆转肥胖细胞中与肥胖相关的缺陷。

据介绍，血红素是许多蛋白质中必不可少的非朊基组分，是许多生理过程的主要信号分子。血红素的化学反应需要细胞内伴侣蛋白网络来避免游离血红素的细胞毒作用，但是这种运输途径的组成是未知的。血红素的合成在线粒体中完成，亚铁螯合酶将铁添加到原卟啉IX中。目前关于这种至关重要但反应性强的代谢物如何在细胞内从线粒体转运到血红蛋白仍然知之甚少。

附：英文原文

Title: PGRMC2 is an intracellular haem chaperone critical for adipocyte function

Author: Andrea Galmozzi, Bernard P. Kok, Arthur S. Kim, J. Rafael Montenegro-Burke, Jae Y. Lee, Roberto Spreafico, Sarah Mosure, Verena Albert, Rigo Cintron-Colon, Cristina Godio, William R. Webb, Bruno Conti, Laura A. Solt, Douglas Kojetin, Christopher G. Parker, John J. Peluso, James K. Pru, Gary Siuzdak, Benjamin F. Cravatt, Enrique Saez

Issue&Volume: 2019-11-20

Abstract: Haem is an essential prosthetic group of numerous proteins and a central signalling molecule in many physiologic processes1,2. 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 unknown3,4. 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 defined3,4. 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 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. Progesterone receptor membrane component 2 is required to transport haem from the mitochondria to the nucleus, where, in adipose tissue, it has roles in regulation of thermogenesis and glucose metabolism.

DOI: 10.1038/s41586-019-1774-2

Source:https://www.nature.com/articles/s41586-019-1774-2