Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation.
Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation.
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DOI：
10.1016/j.immuni.2015.10.005
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发表时间：
2015-10-20
期刊：
影响因子：
32.4
通讯作者：
Xavier RJ
中科院分区：
文献类型：
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作者：
Cao Z;Conway KL;Heath RJ;Rush JS;Leshchiner ES;Ramirez-Ortiz ZG;Nedelsky NB;Huang H;Ng A;Gardet A;Cheng SC;Shamji AF;Rioux JD;Wijmenga C;Netea MG;Means TK;Daly MJ;Xavier RJ
CARD9是通过C型凝集素受体的抗真菌先天免疫信号传导的中心组分，并且几种免疫相关疾病与CARD9突变相关。在这里，我们使用了一种罕见的CARD9变体，它可以保护人们免受炎症性肠病的侵害，作为研究CARD9调控的切入点。我们发现C末端截短的CARD 9保护性变体以显性负性方式作用于CARD 9介导的细胞因子产生，这表明C末端在CARD 9信号传导中发挥重要作用。我们将TRIM62鉴定为CARD9结合伴侣，并表明TRIM62促进了CARD9的K27连接的多聚泛素化。我们鉴定了K125作为CARD9上的泛素化残基，并证明这种泛素化对于CARD9活性是必不可少的。此外，我们发现Trim62缺陷小鼠对真菌感染的易感性增加，与Card9缺陷小鼠相似。这项研究利用一种罕见的保护性等位基因来揭示TRIM62介导的调节CARD9激活的机制。
CARD9 is a central component of anti-fungal innate immune signaling via C-type lectin receptors, and several immune-related disorders are associated with CARD9 mutations. Here we used a rare CARD9 variant that confers protection against inflammatory bowel disease as an entry point to investigate CARD9 regulation. We showed that the C-terminal truncated CARD9 protective variant acted in a dominant negative manner for CARD9-mediated cytokine production, indicating an important role for the C terminus in CARD9 signaling. We identified TRIM62 as a CARD9 binding partner and showed that TRIM62 facilitated K27-linked poly-ubiquitination of CARD9. We identified K125 as the ubiquitinated residue on CARD9 and demonstrated that this ubiquitination was essential for CARD9 activity. Furthermore, we showed that Trim62-deficient mice have increased susceptibility to fungal infection, similar to Card9-deficient mice. This study utilizes a rare protective allele to uncover a TRIM62-mediated mechanism for regulation of CARD9 activation.