Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Nature. 2010 Feb 25;463(7284):1092-5. doi: 10.1038/nature08762.
The detection and compensatory response to the accumulation of unfolded proteins in the endoplasmic reticulum (ER), termed the unfolded protein response (UPR), represents a conserved cellular homeostatic mechanism with important roles in normal development and in the pathogenesis of disease. The IRE1-XBP1/Hac1 pathway is a major branch of the UPR that has been conserved from yeast to human. X-box binding protein 1 (XBP1) is required for the differentiation of the highly secretory plasma cells of the mammalian adaptive immune system, but recent work also points to reciprocal interactions between the UPR and other aspects of immunity and inflammation. We have been studying innate immunity in the nematode Caenorhabditis elegans, having established a principal role for a conserved PMK-1 p38 mitogen-activated protein kinase (MAPK) pathway in mediating resistance to microbial pathogens. Here we show that during C. elegans development, XBP-1 has an essential role in protecting the host during activation of innate immunity. Activation of the PMK-1-mediated response to infection with Pseudomonas aeruginosa induces the XBP-1-dependent UPR. Whereas a loss-of-function xbp-1 mutant develops normally in the presence of relatively non-pathogenic bacteria, infection of the xbp-1 mutant with P. aeruginosa leads to disruption of ER morphology and larval lethality. Unexpectedly, the larval lethality phenotype on pathogenic P. aeruginosa is suppressed by loss of PMK-1-mediated immunity. Furthermore, hyperactivation of PMK-1 causes larval lethality in the xbp-1 mutant even in the absence of pathogenic bacteria. Our data establish innate immunity as a physiologically relevant inducer of ER stress during C. elegans development and indicate that an ancient, conserved role for XBP-1 may be to protect the host organism from the detrimental effects of mounting an innate immune response to microbes.
内质网（ER）中未折叠蛋白积累的检测和补偿反应，称为未折叠蛋白反应（UPR），是一种保守的细胞内稳态机制，在正常发育和疾病发病机制中具有重要作用。IRE1-XBP1/Hac1 途径是 UPR 的一个主要分支，从酵母到人类都有保守。X 盒结合蛋白 1（XBP1）是哺乳动物适应性免疫系统高度分泌性浆细胞分化所必需的，但最近的工作也指出 UPR 与免疫和炎症的其他方面之间存在相互作用。我们一直在研究线虫秀丽隐杆线虫的先天免疫，已经确定了保守的 PMK-1 p38 丝裂原激活蛋白激酶（MAPK）途径在介导对微生物病原体的抗性方面的主要作用。在这里，我们显示在秀丽隐杆线虫发育过程中，XBP-1 在激活先天免疫过程中保护宿主方面具有重要作用。假单胞菌感染激活 PMK-1 介导的反应诱导 XBP-1 依赖性 UPR。虽然在相对非致病性细菌存在的情况下，xbp-1 功能丧失突变体正常发育，但 xbp-1 突变体感染铜绿假单胞菌会导致 ER 形态破坏和幼虫致死。出乎意料的是，致病性铜绿假单胞菌的幼虫致死表型被 PMK-1 介导的免疫缺失所抑制。此外，即使在没有致病性细菌的情况下，PMK-1 的过度激活也会导致 xbp-1 突变体的幼虫死亡。我们的数据确立了先天免疫是秀丽隐杆线虫发育过程中 ER 应激的生理相关诱导因素，并表明 XBP-1 的古老、保守作用可能是保护宿主免受微生物先天免疫反应的不利影响。
