Survive an innate immune response through XBP1.
Survive an innate immune response through XBP1.
复制标题
通过 XBP1 抵抗先天免疫反应。
DOI：
10.1038/cr.2010.61
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发表时间：
2010
期刊：
影响因子：
44.1
通讯作者：
Blumberg,RichardS
中科院分区：
文献类型：
--
作者：
Kaser,Arthur;Blumberg,RichardS
内质网（ER）应激发生在未折叠或错误折叠的蛋白质积累时，并诱导适应性机制，称为未折叠蛋白质反应（UPR），旨在解决ER应激，从而防止潜在功能失调的蛋白质损害适当的细胞功能[1]。UPR一般是一种进化上高度保守的机制，特别是有一个分支（IRE 1-XBP 1轴）从酵母到包括人类在内的后生动物都是保守的。虽然高度分泌细胞特别依赖于有效的UPR，但同样明显的是，影响蛋白质折叠的多种次要因素可能导致错误折叠蛋白质的积累，从而导致ER应激;这些因素包括细胞的代谢状态、氧供应、氧化还原状态和许多其他因素[1]。Richardson等人的一项有趣的研究现在报道说，先天免疫激活是秀丽隐杆线虫（C. habditis elegans）ER应激的一个有效触发因素。elegans），其中UPR的依赖于XBP 1的分支是从与引发先天免疫应答相关的应激中恢复并存活所必需的[2]。具体而言，铜绿假单胞菌（P. aeruginosa）感染诱导继发于PMK-1激活的ER应激[2]，PMK-1是p38促分裂原活化蛋白激酶（MAPK）的直向同源物，此前已证明其对微生物病原体的抗性至关重要[3]。与野生型幼虫相反，功能丧失型xbp-1突变体在铜绿假单胞菌感染后表现出幼虫致死性，这与ER形态的破坏有关。相当令人惊讶的是，在不存在p38 PMK-1的情况下没有发生幼虫致死。然而，在功能丧失的xbp-1突变体的背景下，在不存在病原菌的情况下，通过沉默vhp-1（一种MAPK磷酸酶）过度激活PMK-1，重现了上述致死表型[2]。xbp-1不影响铜绿假单胞菌的蓄积速率，排除了xbp-1功能丧失后的发育致死性可归因于加速感染的可能性[2]。此外，UPR的另外两个分支（atf-6和pek-1）的功能丧失对铜绿假单胞菌存在下的幼虫发育没有影响[2]，将IRE 1-XBP 1轴鉴定为继发于先天免疫应答诱导的关键保护性UPR分支。
Endoplasmic reticulum (ER) stress occurs upon the accumulation of unfolded or misfolded proteins, and induces adaptive mechanisms, termed the unfolded protein response (UPR), aimed at resolving ER stress and hence preventing potentially dysfunctional proteins from impairing proper cell function [1]. The UPR in general is an evolutionary highly conserved mechanism, with one branch in particular (the IRE1-XBP1 axis) conserved from yeast to metazoans including man. While highly secretory cells are particularly dependent upon an efficient UPR, it is also obvious that a multitude of secondary factors that affect protein folding may lead to the accumulation of misfolded proteins and hence ER stress; these factors include the metabolic state of the cell, oxygen supply, redox state, and many others [1]. An intriguing study by Richardson et al. now reports that innate immune activation is a potent trigger of ER stress in Caenorhabditis elegans (C. elegans), with the XBP1-dependent branch of the UPR being required to recover from and survive the stress associated with the elicitation of an innate immune response [2]. Specifically, infection with Pseudomonas aeruginosa (P. aeruginosa) induced ER stress secondary to activation of PMK-1 [2], the p38 mitogen-activated protein kinase (MAPK) orthologue which had previously been shown to be essential for resistance against microbial pathogens [3]. In contrast to wild-type larvae, loss-offunction xbp-1 mutants exhibited larval lethality upon P. aeruginosa infection, which was associated with disruption of ER morphology. Quite surprisingly, larval lethality did not occur in the absence of p38 PMK-1. However, overactivation of PMK-1 in the absence of pathogenic bacteria via silencing of vhp-1, a MAPK phosphatase, in the context of loss-offunction xbp-1 mutants recapitulated the lethal phenotype described above [2]. xbp-1 did not affect the rate of accumulation of P. aeruginosa, excluding the possibility that developmental lethality upon xbp-1 loss-of-function is attributable to accelerated infection [2]. Moreover, loss-of-function in the two other branches of the UPR (atf-6 and pek-1) had no effect on larval development in the presence of P. aeruginosa [2], identifying the IRE1-XBP1 axis as the critical protective UPR branch induced secondary to an innate immune response.