细胞内质网应激信号通路在代谢适应性调节中的生理学功能与机制

In eukaryotic cells, the endoplasmic reticulum (ER) is the primary site for protein folding, maturation and quality control. Accumulation of unfolded/misfolded proteins in the ER lumen causes ER stress and initiates the cellular unfolded protein response (UPR). The ER-localized transmembrane protein IRE1 (inositol-requiring enzyme 1) possesses both protein Ser/Thr kinase and endoribonuclease (RNase) activities, which mediates a key signaling branch of the UPR. Under ER stress conditions, IRE1 is activated through dimerization and trans-autophosphorylation, resulting in the non-conventional splicing of XBP1 (X-box binding protein 1) mRNA to yield an active form of this transcription factor that induces a major transcriptional program of the UPR. We previously found that IRE1alpha could be activated in response to changes of the nutritional states and metabolic cues. Here we hypothesize that the IRE1alpha pathway plays crucial physiological roles in metabolic adaptation and flexibility. We aim to employ tissue-specific gene-targeting strategies and investigate the metabolic regulatory functions of IRE1alpha in the liver and adipose tissue. We also attempt to explore the molecular effectors as well as the signaling mechanisms of IRE1alpha action in the control of glucose and lipid metabolism. These studies will help elucidate the molecular connection between ER stress and metabolic dysfunctions, and provide a new paradigm with respect to the mechanism that underlies metabolic adaptation and pathogenic progression of metabolic disorders.

内质网是真核细胞中蛋白质折叠、加工及质量监控的重要场所。当细胞难以承担内质网中未折叠蛋白的负荷时即发生内质网应激，通过激活未折叠蛋白响应以维持其正常功能。内质网跨膜蛋白IRE1α是应对内质网应激的关键信号分子，集激酶与核糖核酸酶于一体，能通过非常规的mRNA剪切控制下游XBP1转录因子的活性。内质网应激与糖脂代谢异常密切相关，而我们在前期研究中也发现IRE1α受特定代谢信号的刺激调控。由此我们设想：IRE1α不仅是蛋白折叠、也是机体营养与代谢状况的分子感应器，在糖脂代谢平衡中可能发挥重要的调节作用。我们拟利用组织特异性IRE1α敲除的小鼠模型，研究IRE1α在肝脏和脂肪组织中的代谢功能，探索IRE1α参与代谢调控的下游效应分子和信号机制，揭示IRE1α通路在应对代谢应激过程中的生理学作用。这些研究将有助于我们深入了解内质网应激与代谢紊乱的机制关联，为解析代谢性疾病的分子基础提供新的线索。

内质网是真核细胞中蛋白质折叠、加工与质量监控以及脂质合成的重要细胞器。当细胞难以承担内质网中未折叠蛋白的负荷时即发生内质网应激，通过激活未折叠蛋白响应以维持其正常功能。大量研究表明，内质网应激与机体糖脂代谢的异常密切相关。内质网跨膜蛋白IRE1α是应对内质网应激的关键信号分子，其胞内段具有蛋白激酶与核糖核酸内切酶的双重活性，通过非常规mRNA剪切来调节下游XBP1转录因子的活性。我们从前期研究发现的IRE1α受特定代谢信号刺激的调控这一现象出发，提出了“IRE1α不仅是蛋白折叠、也是机体营养与代谢状况分子感应器”的设想，深入探索了IRE1α在代谢平衡调节中发挥的重要生理学作用。我们利用组织特异性IRE1α敲除的小鼠模型，在营养缺失或营养过剩条件下，剖析了IRE1α在肝脏、脂肪组织、胰岛以及巨噬细胞中感应机体营养状况进而参与调节机体能量平衡与糖脂代谢的功能，并揭示了IRE1α行使这些调控功能的分子机制；同时，还研究了IRE1α感应肝脏损伤进而调节肝脏修复再生过程的功能与机制。这些系统性研究结果表明，IRE1α通路在代谢应激适应性转变过程中发挥至关重要的生理学作用。此项研究进一步加深并拓展了我们对内质网应激与代谢紊乱发生机制的了解，为全面解析肥胖与代谢性疾病的分子基础提供了新的线索和思路。