DDX58/IFIH1-mediated induction of interferon-alpha/beta

RIG-I-like helicases (RLHs) the retinoic acid inducible gene-I (RIG-I, DDX58) and melanoma differentiation associated gene 5 (MDA5, IFIH1) are RNA helicases that recognize viral double-stranded RNA (dsRNA) present within the cytoplasm (Yoneyama M & Fujita T 2007, 2008). Upon viral infection dsRNA is generated by positive-strand RNA virus families such as Flaviviridae and Coronaviridae, negative-strand RNA virus families including Orthomyxoviridae and Paramyxoviridae, and DNA virus families such as Herpesviridae and Adenoviridae (Weber F et al. 2006; Son KN et al. 2015). Functionally RIG-I (DDX58) and MDA5 (IFIH1) positively regulate the IFN genes in a similar fashion, however they differ in their response to different viral species. DDX58 (RIG-I) is essential for detecting influenza virus, Sendai virus, VSV and Japanese encephalitis virus (JEV), whereas IFIH1 (MDA5) is essential in sensing encephalomyocarditis virus (EMCV), Mengo virus and Theiler's virus, all of which belong to the picornavirus family. RIG-I and MDA5 signalling results in the activation of IKK epsilon and (TKK binding kinase 1) TBK1, two serine/threonine kinases that phosphorylate interferon regulatory factor 3 and 7 (IRF3 and IRF7). Upon phosphorylation, IRF3 and IRF7 translocate to the nucleus and subsequently induce interferon alpha (IFNA) and interferon beta (IFNB) gene transcription (Yoneyama M et al. 2004; Yoneyama M & Fujita T 2007, 2008).

RIG-I样螺旋酶（RLHs），包括视黄酸诱导基因-I（RIG-I，DDX58）和黑色素瘤分化相关基因5（MDA5，IFIH1），均为识别细胞质内存在的病毒双链RNA（dsRNA）的RNA螺旋酶（Yoneyama M & Fujita T, 2007, 2008）。在病毒感染过程中，正链RNA病毒家族如黄病毒科和冠状病毒科、负链RNA病毒家族包括正黏病毒科和副黏病毒科，以及DNA病毒家族如疱疹病毒科和腺病毒科等均能产生dsRNA（Weber F et al., 2006; Son KN et al., 2015）。在功能上，RIG-I（DDX58）与MDA5（IFIH1）均以类似方式正向调控IFN基因，但它们对不同的病毒物种的反应存在差异。DDX58（RIG-I）对于检测流感病毒、仙台病毒、水泡性口炎病毒（VSV）和日本脑炎病毒（JEV）至关重要，而IFIH1（MDA5）则在检测小核糖核酸病毒科中的脑心肌炎病毒（EMCV）、孟戈病毒和泰勒病毒时不可或缺。RIG-I和MDA5的信号传导导致丝氨酸/苏氨酸激酶IKK epsilon和（TKK结合激酶1）TBK1的激活，这两种激酶磷酸化干扰素调节因子3和7（IRF3和IRF7）。磷酸化后，IRF3和IRF7转位至细胞核，进而诱导干扰素α（IFNA）和干扰素β（IFNB）基因的转录（Yoneyama M et al., 2004; Yoneyama M & Fujita T, 2007, 2008）。