Identification of loss of function mutations in human genes encoding RIG-I and MDA5: implications for resistance to type I diabetes.
Identification of loss of function mutations in human genes encoding RIG-I and MDA5: implications for resistance to type I diabetes.
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DOI：
10.1074/jbc.m809449200
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发表时间：
2009-05-15
期刊：
影响因子：
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通讯作者：
Fujita T
中科院分区：
文献类型：
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作者：
Shigemoto T;Kageyama M;Hirai R;Zheng J;Yoneyama M;Fujita T
视黄酸诱导基因I （RIG-I）和黑色素瘤分化相关基因5 （MDA5）对于检测病毒RNA和触发抗病毒反应（包括I型干扰素的产生）至关重要。我们通过细胞培养中的功能互补分析了数据库中报道的人类rig - 1和MDA5的非同义突变体的表型。在RIG-I的7个错义突变中，S183I发生在第二个caspase募集结构域重复序列中，使该结构域失活，并具有显性抑制功能。在MDA5的10个突变体中，有2个表现出功能丧失。无义突变E627*导致c端区域缺失和双链RNA （dsRNA）结合活性降低。另一个发生在c端结构域的功能突变I923V的缺失并未影响dsRNA的结合活性，这表明该残基在信号传导中具有新颖而重要的作用。值得注意的是，这些突变与对1型糖尿病的抵抗力有关。然而，MDA5的A946T突变既不影响dsRNA的结合，也不影响IFN基因的激活，而之前的遗传分析表明，MDA5的A946T突变与I型糖尿病有关。这些结果为rig - i样受体的结构-功能关系以及人类rig - i样受体多态性、抗病毒先天免疫和自身免疫性疾病提供了新的见解。
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.