Identification of Loss of Function Mutations in Human Genes Encoding RIG-I and MDA5 IMPLICATIONS FOR RESISTANCE TO TYPE I DIABETES

被引:126
作者
Shigemoto, Taeko [1 ,2 ]
Kageyama, Maiko [1 ,2 ]
Hirai, Reiko [1 ]
Zheng, JiPing [1 ]
Yoneyama, Mitsutoshi [1 ,2 ,3 ]
Fujita, Takashi [1 ,2 ]
机构
[1] Kyoto Univ, Mol Genet Lab, Inst Virus Res, Kyoto 6068507, Japan
[2] Kyoto Univ, Grad Sch Biostudies, Mol Cell Biol Lab, Kyoto 6068507, Japan
[3] Japan Sci & Technol Agcy, PRESTO, Kawaguchi, Saitama 3320012, Japan
基金
日本科学技术振兴机构;
关键词
ANTIVIRAL RESPONSES; INNATE IMMUNITY; RNA; RECOGNITION; HELICASE; MECHANISM; DOMAIN; ACID; LGP2;
D O I
10.1074/jbc.M809449200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are essential for detecting viral RNA and triggering antiviral responses, including production of type I interferon. We analyzed the phenotype of non-synonymous mutants of human RIG-I and MDA5 reported in databases by functional complementation in cell cultures. Of seven missense mutations of RIG-I, S183I, which occurs within the second caspase recruitment domain repeat, inactivated this domain and conferred a dominant inhibitory function. Of 10 mutants of MDA5, two exhibited loss of function. A nonsense mutation, E627*, resulted in deletion of the C-terminal region and double-stranded RNA (dsRNA) binding activity. Another loss of function mutation, I923V, which occurs within the C-terminal domain, did not affect dsRNA binding activity, suggesting a novel and essential role for this residue in the signaling. Remarkably, these mutations are implicated in resistance to type I diabetes. However, the A946T mutation of MDA5, which has been implicated in type I diabetes by previous genetic analyses, affected neither dsRNA binding nor IFN gene activation. These results provide new insights into the structure-function relationship of RIG-I-like receptors as well as into human RIG-I-like receptor polymorphisms, antiviral innate immunity, and autoimmune diseases.
引用
收藏
页码:13348 / 13354
页数:7
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