The interaction between IKKα and LC3 promotes type I interferon production through the TLR9-containing LAPosome.
The interaction between IKKα and LC3 promotes type I interferon production through the TLR9-containing LAPosome.
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DOI：
10.1126/scisignal.aan4144
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发表时间：
2018-05-01
影响因子：
7.3
通讯作者：
Iwasaki A
中科院分区：
文献类型：
--
作者：
Hayashi K;Taura M;Iwasaki A
Toll样受体9（TLR 9）识别核内体中的DNA并激活不同的信号传导途径以刺激促炎细胞因子和I型干扰素（IFN）的产生。微管相关蛋白1A/1B轻链3B（LC 3）修饰的内体囊泡上的信号平台的组装需要抑制刺激IFN产生的TLR 9信号，而不是白细胞介素-12 p40（IL-12 p40）。LC 3相关吞噬作用（英语：LC 3-associated phagocytosis，缩写：LC 3）是一种非典型的自噬作用，对干扰素调节因子7（IRF 7）的激活和IFN的合成至关重要。我们发现，在CpG寡核苷酸刺激TLR 9后，自噬蛋白LC 3和激酶IKKα被募集到含有TLR 9的内体。IKKα和LC 3向这些信号内体的募集不受经典自噬体形成催化剂的刺激，但涉及ATG 5而不是FIP 200的形成。此外，我们发现LC 3-IKKα复合物进一步与TRAF 3和IRF 7相关。我们在IKKα中鉴定了三个推定的LC 3相互作用区域（LIR），诱变表明其中两个区域对于与LC 3的直接结合至关重要。此外，相同LIR序列的突变不能在IKKα缺陷的树突状细胞重建后拯救I型IFN的产生。总之，这些数据表明，TLR 9激活下游的IKKα募集和IFN α形成之间存在直接联系，这对促进I型IFN的产生是必要的。自噬蛋白LC 3在TLR 9刺激后直接募集激酶IKKα到I型IFN产生所必需的内体平台LC 3在TLR 9活化后募集IKKα Toll样受体9（TLR 9）是一种参与吞噬细胞内体细胞外DNA先天感应的模式识别受体。Hayashi等发现，IKKα激酶与TLR 9刺激巨噬细胞后沉积在核内体上的自噬蛋白LC 3相关。通过非典型自噬形成的LC 3-IKKα信号平台也招募了参与I型干扰素信号传导的其他效应物。IKKα中LC 3相互作用区域的突变表明这些作用是由激酶与LC 3的直接相互作用介导的。总之，这些数据将IKKα确定为LC 3相关吞噬介导的基于内体的信号平台的关键组分，该信号平台是在TLR 9参与后刺激I型干扰素产生所必需的。
Toll-like receptor 9 (TLR9) recognizes DNA in endosomes and activates distinct signaling pathways to stimulate the production of proinflammatory cytokines and type I interferons (IFN). The assembly of signaling platforms on microtubule-associated proteins 1A/1B light chain 3B (LC3)-decorated endosomal vesicles is required to transduce TLR9 signals that stimulate the production of IFN, but not interleukin-12 p40 (IL-12p40). LC3-associated phagocytosis (LAP), a form of noncanonical autophagy, is critical for the activation of interferon regulatory factor 7 (IRF7) and for IFN synthesis. Here we showed that, after the stimulation of TLR9 by CpG oligonucleotides, the autophagy protein LC3 and the kinase IKKα were recruited to endosomes that contained TLR9. The recruitment of IKKα and LC3 to such signaling endosomes was not stimulated by catalysts of classical autophagosome formation, but involved LAP formation, which required ATG5 but not FIP200. Additionally, we found that the LC3-IKKα complex further associated with both TRAF3 and IRF7. We identified three putative LC3-interacting regions (LIRs) in IKKα, and mutagenesis suggested that two of these were critical for direct binding to LC3. Moreover, mutation of the same LIR sequences failed to rescue type I IFN production in IKKα-deficient dendritic cells upon reconstitution. Together, these data suggest a direct link between LAP formation and IKKα recruitment downstream of TLR9 activation that is necessary to facilitate type I IFN production. Autophagy protein LC3 directly recruits kinase IKKα to endosomal platforms necessary for type I IFN production after TLR9 stimulation LC3 recruits IKKα after TLR9 activation Toll like receptor 9 (TLR9) is a pattern recognition receptor involved in innate sensing of extracellular DNA within the endosomes of phagocytes. Hayashi, et al found that IKKα kinase associated with the autophagy protein LC3 deposited on endosomes after TLR9 stimulation of macrophages. Formation of this LC3-IKKα signaling platform through non-canonical autophagy also recruited other effectors involved in type I interferon signaling. Mutagenesis of LC3 interacting regions in IKKα suggested these effects were mediated by a direct interaction of the kinase with LC3. Together, these data identify IKKα as a critical component of LC3-associated phagocytosis-mediated endosome-based signaling platforms necessary for stimulating type I interferon production after TLR9 engagement.
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