Integrated Genomics of Crohn's Disease Risk Variant Identifies a Role for CLEC12A in Antibacterial Autophagy.
Integrated Genomics of Crohn's Disease Risk Variant Identifies a Role for CLEC12A in Antibacterial Autophagy.
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DOI：
10.1016/j.celrep.2015.05.045
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发表时间：
2015-06-30
期刊：
影响因子：
8.8
通讯作者：
Xavier RJ
中科院分区：
文献类型：
--
作者：
Begun J;Lassen KG;Jijon HB;Baxt LA;Goel G;Heath RJ;Ng A;Tam JM;Kuo SY;Villablanca EJ;Fagbami L;Oosting M;Kumar V;Schenone M;Carr SA;Joosten LA;Vyas JM;Daly MJ;Netea MG;Brown GD;Wijmenga C;Xavier RJ
与克罗恩病风险增加相关的多态性ATG 16 L1 T300 A损害了病原体防御机制，包括选择性自噬，但风险等位基因改变的特定途径相互作用仍然未知。在这里，我们使用人外周血细胞的扰动分析，揭示CLEC 12 A是在ATG 16 L1-T300 A依赖的方式进行调节。CLEC 12 A缺陷细胞中的抗菌自噬受损，并且在存在ATG 16 L1 β 300 A风险等位基因的情况下，这种作用加剧。Clec 12 a −/−小鼠对沙门氏菌感染更敏感，支持CLEC 12 A在体内抗菌防御途径中的作用。CLEC 12 A被募集到细菌进入位点、细菌-自噬体复合物和无菌膜损伤位点。整合基因组学鉴定了CLEC 12 A和在抗菌自噬中起作用的E3-泛素连接酶复合物之间的功能性相互作用。这些数据将CLEC 12 A鉴定为抗菌自噬的早期衔接分子，并强调扰动谱作为阐明复杂遗传疾病中防御途径的方法。整合基因组学揭示风险等位基因特异性自噬途径相互作用CLEC 12 A对上皮细胞和免疫细胞中的抗菌自噬很重要CLEC 12 A敲低放大了ATG 16 L1细胞中的抗菌自噬缺陷Clec 12 a −/−小鼠体内更容易受到沙门氏菌感染尽管全基因组关联研究在识别疾病相关位点方面很有价值，但它们只能产生发病机制的部分观点。使用整合的系统水平方法来确定与克罗恩病相关变体ATG 16 L1 T300 A相互作用的基因，Begun et al.将CLEC 12 A鉴定为在抗菌自噬中起作用的先天防御基因。
The polymorphism ATG16L1 T300A, associated with increased risk of Crohn’s disease, impairs pathogen defense mechanisms including selective autophagy, but specific pathway interactions altered by the risk allele remain unknown. Here, we use perturbational profiling of human peripheral blood cells to reveal that CLEC12A is regulated in an ATG16L1-T300A-dependent manner. Antibacterial autophagy is impaired in CLEC12A-deficient cells, and this effect is exacerbated in the presence of the ATG16L1∗300A risk allele. Clec12a−/− mice are more susceptible to Salmonella infection, supporting a role for CLEC12A in antibacterial defense pathways in vivo. CLEC12A is recruited to sites of bacterial entry, bacteria-autophagosome complexes, and sites of sterile membrane damage. Integrated genomics identified a functional interaction between CLEC12A and an E3-ubiquitin ligase complex that functions in antibacterial autophagy. These data identify CLEC12A as early adaptor molecule for antibacterial autophagy and highlight perturbational profiling as a method to elucidate defense pathways in complex genetic disease. Integrated genomics reveals risk-allele-specific autophagy pathway interactions CLEC12A is important for antibacterial autophagy in epithelial and immune cells CLEC12A knockdown amplifies antibacterial autophagy defects in ATG16L1 ∗300A cells Clec12a−/− mice are more susceptible to Salmonella infection in vivo Although genome-wide association studies are valuable in identifying disease-associated loci, they produce only a partial view of pathogenesis. Using integrated, systems-level approaches to pinpoint genes that interact with the Crohn’s-disease-associated variant ATG16L1 T300A, Begun et al. identify CLEC12A as an innate defense gene that functions in antibacterial autophagy.