ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn's disease pathogenesis.
ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn's disease pathogenesis.
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DOI：
10.1053/j.gastro.2010.07.006
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发表时间：
2010-11
期刊：
影响因子：
29.4
通讯作者：
McDonald C
中科院分区：
文献类型：
--
作者：
Homer CR;Richmond AL;Rebert NA;Achkar JP;McDonald C
许多基因的鉴定赋予克罗恩病（CD）的易感性表明，这种复杂的疾病可能是由几个基因的相关功能的改变。我们研究了CD风险基因自噬相关16样蛋白1（ATG 16 L1）和核苷酸结合寡聚化结构域2（NOD 2）之间的功能相互作用，以确定疾病相关变体改变的自噬依赖性途径。我们通过免疫印迹、共聚焦显微镜、流式细胞术、报告基因和庆大霉素保护试验，在人上皮细胞系和来自健康个体的原代人巨噬细胞和树突状细胞中评估了胞壁酰二肽（MDP）对Nod 2信号传导和自噬激活的响应。在通过RNA干扰、抑制剂或ATG 16 L1或NOD 2变体操作的细胞系中以及在来自健康基因型供体的原代巨噬细胞和树突状细胞中，评估了Nod 2和ATG 16 L1表达的需求以及CD相关变体在MDP刺激的自噬和Nod 2依赖性信号传导中的作用。MDP刺激上皮细胞、巨噬细胞和树突状细胞激活自噬和NF-κB和MAPK信号传导;它还增加了对沙门氏菌的杀伤。这些反应依赖于ATG 16 L1和Nod 2的表达，并受到CD相关的NOD 2变体的损害。在具有与CD相关的ATG 16 L1 T300 A基因型的细胞中，Nod 2依赖性信号传导未受损。然而，ATG 16 L1 T300 A变体仅在上皮细胞系中阻断了MDP介导的沙门氏菌杀伤的增加，而不是原代巨噬细胞或树突状细胞。ATG 16 L1和NOD 2是自噬介导的抗菌途径的组分，其通过CD相关突变以细胞和功能特异性方式改变。
The identification of numerous genes that confer susceptibility to Crohn’s disease (CD) indicates that this complex disease might arise from alterations in several genes with related functions. We examined the functional interaction between the CD risk genes autophagy-related 16-like protein 1 (ATG16L1) and nucleotide-binding oligomerization domain 2 (NOD2) to identify an autophagy-dependent pathway that is altered by disease-associated variants. We assessed Nod2 signaling and autophagy activation in response to muramyl dipeptide (MDP) by immunoblot, confocal microscopy, flow cytometry, reporter gene, and gentamycin protection assays in human epithelial cell lines and primary human macrophages and dendritic cells from healthy individuals. The requirement of Nod2 and ATG16L1 expression and the effects of CD-associated variants in MDP-stimulated autophagy and Nod2-dependent signaling were assessed in cell lines manipulated by RNA interference, inhibitors, or ATG16L1 or NOD2 variants and in primary macrophages and dendritic cells from healthy, genotyped donors. MDP stimulation of epithelial cells, macrophages, and dendritic cells activated autophagy and NF-κB and MAPK signaling; it also increased killing of Salmonella. These responses depended on ATG16L1 and Nod2 expression and were impaired by CD-associated NOD2 variants. Nod2-dependent signaling was not impaired in cells with the ATG16L1 T300A genotype, which is associated with CD. However, the ATG16L1 T300A variant blocked the increase in MDP-mediated killing of Salmonella only in epithelial cell lines and not primary macrophages or dendritic cells. ATG16L1 and NOD2 are components of an autophagy-mediated, anti-bacterial pathway that is altered in a cell- and function-specific manner by CD-associated mutations.
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影响因子：
30.8
作者：
Hampe, Jochen;Franke, Andre;Schreiber, Stefan
通讯作者：
Schreiber, Stefan
影响因子：
30.5
作者：
Franchi, Luigi;Amer, Amal;Nunez, Gabriel
通讯作者：
Nunez, Gabriel
DOI：
10.1073/pnas.0907722106
发表时间：
2009-09-15
影响因子：
11.1
作者：
Petnicki-Ocwieja, Tanja;Hrncir, Tomas;Kobayashi, Koichi S.
通讯作者：
Kobayashi, Koichi S.
DOI：
10.4049/jimmunol.0802197
发表时间：
2009-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Marina-García N;Franchi L;Kim YG;Hu Y;Smith DE;Boons GJ;Núñez G
通讯作者：
Núñez G
影响因子：
24.5
作者：
Massey, Dunecan;Parkes, Miles
通讯作者：
Parkes, Miles