An essential role for XBP-1 in host protection against immune activation in C. elegans.
An essential role for XBP-1 in host protection against immune activation in C. elegans.
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对内质网（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），代表了一种保守的细胞稳态机制，在正常发育和疾病发病机制中发挥着重要作用。 IRE1-XBP1/Hac1p 途径是 UPR 的一个主要分支，从酵母到人类都是保守的。 XBP-1 是哺乳动物适应性免疫系统的高分泌性浆细胞分化所必需的，但最近的工作也指出了 UPR 与免疫和炎症的其他方面之间的相互作用。我们一直在研究线虫秀丽隐杆线虫的先天免疫，并确定了保守的 PMK-1 p38 丝裂原激活蛋白激酶 (MAPK) 途径在介导微生物病原体抗性中的关键作用。在这里，我们表明，在秀丽隐杆线虫发育过程中，XBP-1 在先天免疫激活过程中保护宿主方面发挥着重要作用。 PMK-1 介导的铜绿假单胞菌感染反应的激活会诱导 XBP-1 依赖性 UPR。虽然功能丧失的 xbp-1 突变体在相对非致病性细菌存在的情况下正常发育，但铜绿假单胞菌感染 xbp-1 突变体会导致 ER 形态破坏和幼虫致死率。出乎意料的是，致病性铜绿假单胞菌的幼虫致死表型因 PMK-1 介导的免疫力丧失而受到抑制。此外，即使在没有病原菌的情况下，PMK-1 的过度激活也会导致 xbp-1 突变体幼虫死亡。我们的数据表明，先天免疫是线虫发育过程中内质网应激的生理相关诱导剂，并表明 XBP-1 的一个古老而保守的作用可能是保护宿主生物体免受对微生物产生先天免疫反应的有害影响。
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/Hac1p pathway is a major branch of the UPR that has been conserved from yeast to human. XBP-1 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 key 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 suggest 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.
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DOI：
10.1126/science.1166527
发表时间：
2009-01-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Reddy KC;Andersen EC;Kruglyak L;Kim DH
通讯作者：
Kim DH
影响因子：
64.8
作者：
Reimold, AM;Iwakoshi, NN;Glimcher, LH
通讯作者：
Glimcher, LH
影响因子：
64.5
作者：
Shen, XH;Ellis, RE;Kaufman, RJ
通讯作者：
Kaufman, RJ
DOI：
10.1073/pnas.96.2.715
发表时间：
1999-01-19
影响因子：
11.1
作者：
Tan, MW;Mahajan-Miklos, S;Ausubel, FM
通讯作者：
Ausubel, FM
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D