Lipid bilayer stress-activated IRE-1 modulates autophagy during endoplasmic reticulum stress

Metabolic disorders such as obesity and nonalcoholic fatty liver disease (NAFLD) are emerging disorders that affect the global population. One facet of the disorders is attributed to the disturbance of membrane lipid homeostasis. Perturbation of endoplasmic reticulum (ER) homeostasis through changes in membrane phospholipid composition results in activation of the unfolded protein response (UPR) and causes dramatic translational and transcriptional changes in cell. To restore cellular homeostasis, the three highly conserved UPR transducers ATF6, IRE1, and PERK mediate cellular processes upon ER stress. The roles of the UPR in proteostatic stress caused by the accumulation of misfolded protein is well understood but lipid perturbation-induced UPR remains elusive. We found that genetically attenuated PC synthesis in C. elegans causes lipid droplets accumulation if not for the intervention of the UPR program. Transcriptional profiling of lipid perturbation-induced ER stress animals shows a unique subset of genes modulated in an UPR-dependent manner that are unaffected by proteostatic stress. Among these, we identified IRE1-modulated autophagy genes that trigger liberation of free fatty acids from excess lipid droplets suggesting a stress release mechanism by which free fatty acids are rechannelling to restore lipid homeostasis. Considering the important role of lipid homeostasis and how its impairment contributes to the pathologies in metabolic diseases, our data uncovers the indispensable role of a fully functional UPR program in regulating lipid homeostais in the face of chronic ER stress.肥胖、非酒精性脂肪性肝病（nonalcoholic fatty liver disease, NAFLD）等代谢性疾病已成为影响全球人群的新兴疾病。此类疾病的发病机制之一与膜脂稳态失衡密切相关。膜磷脂组成改变引发内质网（endoplasmic reticulum, ER）稳态紊乱，可激活未折叠蛋白反应（unfolded protein response, UPR），并导致细胞内翻译与转录层面的显著变化。为恢复细胞稳态，三种高度保守的UPR转导因子ATF6、IRE1及PERK可介导内质网应激下的细胞应答过程。未折叠蛋白反应（UPR）在错误折叠蛋白积累引发的蛋白稳态应激中的作用已被广泛阐明，但脂扰动诱导的UPR机制仍有待揭示。我们发现，若未通过UPR程序进行干预，秀丽隐杆线虫（C. elegans）中经遗传操作减弱的磷脂酰胆碱（phosphatidylcholine, PC）合成会导致脂滴（lipid droplets）积累。对脂扰动诱导内质网应激的动物进行转录谱分析（transcriptional profiling）后发现，存在一组独特的基因以UPR依赖的方式被调控，且此类基因不受蛋白稳态应激的影响。在此类基因中，我们鉴定出受IRE1调控的自噬（autophagy）基因，此类基因可触发过量脂滴释放游离脂肪酸，这提示存在一种应激释放机制：游离脂肪酸通过该机制被重新定向以恢复脂稳态。鉴于脂稳态的重要作用及其失衡如何参与代谢疾病的病理进程，我们的研究揭示了功能完整的UPR程序在慢性内质网应激下调控脂稳态过程中不可或缺的作用。