Interleukin-1 receptor-associated kinase-2 (IRAK2) is a critical mediator of endoplasmic reticulum (ER) stress signaling.
Interleukin-1 receptor-associated kinase-2 (IRAK2) is a critical mediator of endoplasmic reticulum (ER) stress signaling.
复制标题
DOI：
10.1371/journal.pone.0064256
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Reed JC
中科院分区：
文献类型：
--
作者：
Benosman S;Ravanan P;Correa RG;Hou YC;Yu M;Gulen MF;Li X;Thomas J;Cuddy M;Matsuzawa Y;Sano R;Diaz P;Matsuzawa S;Reed JC
当未折叠蛋白质在细胞器腔中积累时，就会发生内质网（ER）应激，触发信号转导事件，从而促进细胞适应和恢复，或者导致细胞功能障碍和死亡。内质网应激与多种疾病有关。为了鉴定内质网应激的新型调节剂，我们对激酶组进行了 siRNA 文库筛选，揭示了白细胞介素 1 受体相关激酶 2 (IRAK2) 作为未折叠蛋白反应 (UPR) 信号传导和内质网应激诱导的细胞死亡的贡献者。在培养的哺乳动物细胞中敲低IRAK2（但不是IRAK1）的表达可以抑制内质网应激诱导的促凋亡转录因子CHOP的表达和应激激酶的激活。同样，RNAi介导的IRAK家族成员Tube（但不是Pelle）的沉默抑制了果蝇细胞中内质网应激诱导的应激激酶信号的激活。 IRAK2 的作用映射到 IRE1 通路，而不是 UPR 的 PERK 或 ATF6 成分。有趣的是，ER应激还以IRE1/XBP1依赖性方式诱导IRAK2基因表达，表明IRAK2和IRE1存在相互支持的放大环路。在体内，ER 应激诱导小鼠 Irak2 表达。此外，Irak2 基因敲除小鼠的 ER 应激诱导的 CHOP 表达和 IRE1 通路信号传导存在缺陷。这些发现证明了先天免疫机制与 UPR 信号传导之间存在意想不到的联系，揭示了 IRAK2 作为 IRE1 途径的新型放大器。
Endoplasmic reticulum (ER) stress occurs when unfolded proteins accumulate in the lumen of the organelle, triggering signal transduction events that contribute either to cellular adaptation and recovery or alternatively to cellular dysfunction and death. ER stress has been implicated in numerous diseases. To identify novel modulators of ER stress, we undertook a siRNA library screen of the kinome, revealing Interleukin-1 Receptor-Associated Kinase-2 (IRAK2) as a contributor to unfolded protein response (UPR) signaling and ER stress-induced cell death. Knocking down expression of IRAK2 (but not IRAK1) in cultured mammalian cells suppresses ER stress-induced expression of the pro-apoptotic transcription factor CHOP and activation of stress kinases. Similarly, RNAi-mediated silencing of the IRAK family member Tube (but not Pelle) suppresses activation of stress kinase signaling induced by ER stress in Drosophila cells. The action of IRAK2 maps to the IRE1 pathway, rather than the PERK or ATF6 components of the UPR. Interestingly, ER stress also induces IRAK2 gene expression in an IRE1/XBP1-dependent manner, suggesting a mutually supporting amplification loop involving IRAK2 and IRE1. In vivo, ER stress induces Irak2 expression in mice. Moreover, Irak2 gene knockout mice display defects in ER stress-induced CHOP expression and IRE1 pathway signaling. These findings demonstrate an unexpected linkage of the innate immunity machinery to UPR signaling, revealing IRAK2 as a novel amplifier of the IRE1 pathway.
登录
查看更多内容
影响因子：
2.8
作者：
LOOP, SM;ROZANSKI, TA;OSTENSON, RC
通讯作者：
OSTENSON, RC
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D
影响因子：
5.7
作者：
Ravanan P;Sano R;Talwar P;Ogasawara S;Matsuzawa S;Cuddy M;Singh SK;Rao GS;Kondaiah P;Reed JC
通讯作者：
Reed JC
影响因子：
64.5
作者：
Puthalakath, Hamsa;O'Reilly, Lorraine A.;Strasser, Andreas
通讯作者：
Strasser, Andreas
影响因子：
4.8
作者：
Keating, Sinead E.;Maloney, Geraldine M.;Bowie, Andrew G.
通讯作者：
Bowie, Andrew G.