Department of Immunology, University of Toronto, Toronto M5S1A8, Canada.
Immunity. 2013 Nov 14;39(5):858-73. doi: 10.1016/j.immuni.2013.10.013.
The peptidoglycan sensor Nod2 and the autophagy protein ATG16L1 have been linked to Crohn's disease (CD). Although Nod2 and the related sensor, Nod1, direct ATG16L1 to initiate anti-bacterial autophagy, whether ATG16L1 affects Nod-driven inflammation has not been examined. Here, we uncover an unanticipated autophagy-independent role for ATG16L1 in negatively regulating Nod-driven inflammatory responses. Knockdown of ATG16L1 expression, but not that of ATG5 or ATG9a, specifically enhanced Nod-driven cytokine production. In addition, autophagy-incompetent truncated forms of ATG16L1 regulated Nod-driven cytokine responses. Mechanistically, we demonstrated that ATG16L1 interfered with poly-ubiquitination of the Rip2 adaptor and recruitment of Rip2 into large signaling complexes. The CD-associated allele of ATG16L1 was impaired in its ability to regulate Nod-driven inflammatory responses. Overall, these results suggest that ATG16L1 is critical for Nod-dependent regulation of cytokine responses and that disruption of this Nod1- or Nod2-ATG16L1 signaling axis could contribute to the chronic inflammation associated with CD.
肽聚糖传感器 Nod2 和自噬蛋白 ATG16L1 与克罗恩病 (CD) 有关。尽管 Nod2 和相关传感器 Nod1 可直接将 ATG16L1 引导至起始抗细菌自噬，但 ATG16L1 是否影响 Nod 驱动的炎症尚未得到检验。在这里，我们揭示了 ATG16L1 在负调控 Nod 驱动的炎症反应中一个出人意料的、不依赖于自噬的作用。ATG16L1 表达的敲低，而非 ATG5 或 ATG9a 的敲低，特异性增强了 Nod 驱动的细胞因子产生。此外，自噬无能的 ATG16L1 截断形式也调节了 Nod 驱动的细胞因子反应。在机制上，我们证明了 ATG16L1 干扰 Rip2 衔接子的多泛素化以及 Rip2 进入大信号复合物的募集。CD 相关的 ATG16L1 等位基因在调节 Nod 驱动的炎症反应方面存在缺陷。总体而言，这些结果表明 ATG16L1 对于 Nod 依赖性调节细胞因子反应至关重要，并且破坏这个 Nod1 或 Nod2-ATG16L1 信号轴可能导致与 CD 相关的慢性炎症。
