A Non-Canonical IRAK Signaling Pathway Triggered by DNA Damage.
A Non-Canonical IRAK Signaling Pathway Triggered by DNA Damage.
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DNA 损伤触发的非规范 IRAK 信号通路。
DOI：
10.1101/2023.02.08.527716
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Sidi,Samuel
中科院分区：
文献类型：
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作者：
Li,Yuanyuan;Shah,RichaB;Sarti,Samanta;Belcher,AliciaL;Lee,BrianJ;Gorbatenko,Andrej;Nemati,Francesca;Yu,Ian;Stanley,Zoe;Shao,Zhengping;Silva,JoseM;Zha,Shan;Sidi,Samuel
白细胞介素-1受体（IL-1R）相关激酶（IRAKs）是toll样受体（TLR）和IL-1R信号传导的核心效应器，在先天免疫之外没有报道的作用。我们发现，暴露于电离辐射（IR）下的脊椎动物细胞通过TLR/IL-1R诱导的磷酸化级联镜像顺序激活IRAK4和IRAK1，从而产生有效的抗凋亡反应。然而，ir诱导的IRAK1激活不需要受体或IRAK4/1适配器蛋白MyD88，激活的激酶不是留在细胞质中，而是通过保守的核定位信号立即转运到细胞核。我们确定：双链DNA断裂（DSBs）是这一途径的生物学触发因素；E3泛素连接酶Pellino1作为支架使IRAK4/1激活代替TLR/IL-1R-MyD88；以及促凋亡的PIDDosome （PIDD1-RAIDD-caspase-2）作为细胞核中的关键下游靶点。这些数据描述了一种非规范的IRAK信号通路，源自或起源于TLR信号。这种DSB检测途径也被基因毒性化疗激活，为克服肿瘤对主要癌症治疗的耐药提供了多个可操作的靶点。
Interleukin-1 receptor (IL-1R)-associated kinases (IRAKs) are core effectors of Toll-like receptor (TLR) and IL-1R signaling, with no reported roles outside of innate immunity. We find that vertebrate cells exposed to ionizing radiation (IR) sequentially activate IRAK4 and IRAK1 through a phosphorylation cascade mirroring that induced by TLR/IL-1R, resulting in a potent anti-apoptotic response. However, IR-induced IRAK1 activation does not require the receptors or the IRAK4/1 adaptor protein MyD88, and instead of remaining in the cytoplasm, the activated kinase is immediately transported to the nucleus via a conserved nuclear localization signal. We identify: double-strand DNA breaks (DSBs) as the biologic trigger for this pathway; the E3 ubiquitin ligase Pellino1 as the scaffold enabling IRAK4/1 activation in place of TLR/IL-1R-MyD88; and the pro-apoptotic PIDDosome (PIDD1-RAIDD-caspase-2) as a critical downstream target in the nucleus. The data delineate a non-canonical IRAK signaling pathway derived from, or ancestral to, TLR signaling. This DSB detection pathway, which is also activated by genotoxic chemotherapies, provides multiple actionable targets for overcoming tumor resistance to mainstay cancer treatments.