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ATG16L1 negatively regulates RICK/RIP2-mediated innate immune responses
International Immunology ( IF 4.4 ) Pub Date : 2020-09-10 , DOI: 10.1093/intimm/dxaa062
Hajime Honjo 1 , Tomohiro Watanabe 1 , Yasuyuki Arai 2 , Ken Kamata 1 , Kosuke Minaga 1 , Yoriaki Komeda 1 , Kouhei Yamashita 2 , Masatoshi Kudo 1
Affiliation  

Abstract
Polymorphisms in the autophagy-related protein 16 like 1 (ATG16L1) and nucleotide-binding oligomerization domain 2 (NOD2) genes are associated with Crohn’s disease (CD). Impaired interaction between ATG16L1 and NOD2 underlies CD immunopathogenesis. Although activation of the receptor-interacting serine–threonine kinase (RICK, also known as RIP2), a downstream signaling molecule for NOD2 and multiple toll-like receptors (TLRs), plays a pathogenic role in the development of inflammatory bowel disease, the molecular interaction between ATG16L1 and RICK/RIP2 remains poorly understood. In this study, we examined the physical interaction between ATG16L1 and RICK/RIP2 in human embryonic kidney 293 cells and human monocyte-derived dendritic cells (DCs) expressing excessive and endogenous levels of these proteins, respectively. We established that ATG16L1 binds to RICK/RIP2 kinase domain and negatively regulates TLR2-mediated nuclear factor-kappa B (NF-κB) activation and pro-inflammatory cytokine responses by inhibiting the interaction between TLR2 and RICK/RIP2. Binding of ATG16L1 to RICK/RIP2 suppressed NF-κB activation by down-regulating RICK/RIP2 polyubiquitination. Notably, the percentage of colonic DCs expressing ATG16L1 inversely correlated with IL-6 and TNF-α expression levels in the colon of CD patients. These data suggest that the interaction between ATG16L1 and RICK/RIP2 maintains intestinal homeostasis via the down-regulation of TLR-mediated pro-inflammatory cytokine responses.


中文翻译:

ATG16L1 负调控 RICK/RIP2 介导的先天免疫反应

摘要
自噬相关蛋白 16 like 1 ( ATG16L1 ) 和核苷酸结合寡聚化结构域 2 ( NOD2 ) 的多态性) 基因与克罗恩病 (CD) 相关。ATG16L1 和 NOD2 之间的相互作用受损是 CD 免疫发病机制的基础。虽然受体相互作用的丝氨酸-苏氨酸激酶(RICK,也称为 RIP2)是 NOD2 和多种 toll 样受体(TLR)的下游信号分子,但它在炎症性肠病的发展中发挥着致病作用,但ATG16L1 和 RICK/RIP2 之间的相互作用仍然知之甚少。在这项研究中,我们检查了 ATG16L1 和 RICK/RIP2 在人胚胎肾 293 细胞和人单核细胞衍生的树突状细胞 (DC) 中分别表达过量和内源性水平的这些蛋白质的物理相互作用。我们确定 ATG16L1 与 RICK/RIP2 激酶结构域结合,并通过抑制 TLR2 和 RICK/RIP2 之间的相互作用负调节 TLR2 介导的核因子-κB (NF-κB) 激活和促炎细胞因子反应。ATG16L1 与 RICK/RIP2 的结合通过下调 RICK/RIP2 多泛素化来抑制 NF-κB 活化。值得注意的是,表达ATG16L1的结肠DC的百分比与CD患者结肠中IL-6和TNF-α的表达水平呈负相关。这些数据表明,ATG16L1 和 RICK/RIP2 之间的相互作用通过下调 TLR 介导的促炎细胞因子反应来维持肠道稳态。ATG16L1 与 RICK/RIP2 的结合通过下调 RICK/RIP2 多泛素化来抑制 NF-κB 活化。值得注意的是,表达ATG16L1的结肠DC的百分比与CD患者结肠中IL-6和TNF-α的表达水平呈负相关。这些数据表明,ATG16L1 和 RICK/RIP2 之间的相互作用通过下调 TLR 介导的促炎细胞因子反应来维持肠道稳态。ATG16L1 与 RICK/RIP2 的结合通过下调 RICK/RIP2 多泛素化来抑制 NF-κB 活化。值得注意的是,表达ATG16L1的结肠DC的百分比与CD患者结肠中IL-6和TNF-α的表达水平呈负相关。这些数据表明,ATG16L1 和 RICK/RIP2 之间的相互作用通过下调 TLR 介导的促炎细胞因子反应来维持肠道稳态。
更新日期:2020-09-10
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