RIG-I樣受體（RIG-I like receptors,，RLRs）是一類新發(fā)現(xiàn)的模式識別受體,，能夠識別細(xì)胞質(zhì)中的病毒RNA,，在抗病毒天然免疫中起著重要的作用,。RIG-I樣受體包括3個(gè)成員, 即視黃酸誘導(dǎo)基因I (RIG-I),、黑色素瘤分化相關(guān)基因5 (MDA5)以及LGP2,。在哺乳動(dòng)物中,，LGP2在RIG-I/MDA5介導(dǎo)的信號通路中起著負(fù)調(diào)控作用；然而也有研究表明LGP2作為RIG-I/MDA5信號通路的上游信號在抗病毒感染中起著正調(diào)控的作用,。
在中國科學(xué)院水生生物研究所魚類免疫學(xué)與寄生蟲學(xué)學(xué)科組和蘇格蘭魚類免疫研究中心的合作研究中,，昌鳴先等揭示了RIG-I樣受體MDA5和LGP2在低等脊椎動(dòng)物中的功能,。與哺乳動(dòng)物的MDA5和LGP2相同，魚類的MDA5和LGP2也能結(jié)合病毒雙鏈RNA成分,。然而與哺乳類的LGP2調(diào)控MDA5信號通路的功能不同,，魚類MDA5和LGP2的過表達(dá)均能增強(qiáng)細(xì)胞對病毒的感染；過表達(dá)MDA5對LGP2的蛋白表達(dá)沒有影響,，反之亦然,。這說明魚類MDA5和LGP2在抗病毒反應(yīng)中可能獨(dú)立發(fā)揮作用。
他們進(jìn)一步研究發(fā)現(xiàn),，魚類的LGP2還存在一個(gè)截短形式的剪接異構(gòu)體,。類似于LGP2，LGP2的剪接異構(gòu)體在成纖維細(xì)胞和巨噬細(xì)胞中均可檢測到表達(dá),，且其表達(dá)均能被polyI:C和重組干擾素蛋白的刺激以及單鏈陽性或者陰性RNA病毒的感染所誘導(dǎo),。LGP2的剪接異構(gòu)體不具有抗病毒感染的作用，但是LGP2剪接異構(gòu)體的過表達(dá)能夠抑制LGP2介導(dǎo)的抗病毒蛋白Mx的表達(dá),，這表明LGP2剪接異構(gòu)體在LGP2介導(dǎo)的信號傳導(dǎo)通路中可能起著陰性調(diào)節(jié)的作用,。
該研究得到國家自然科學(xué)基金重點(diǎn)項(xiàng)目（30830083）資助，主要由副研究員昌鳴先等完成,，通訊作者為聶品研究員和鄒鈞(Jun Zou)博士,，相關(guān)論文已于7月21日在線發(fā)表在《病毒學(xué)期刊》（Journal of Virology, 2011, 85: 8403-8412）。(生物谷 Bioon.com)
doi:10.1128/JVI.00445-10
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Expression and Functional Characterization of the RIG-I-Like Receptors MDA5 and LGP2 in Rainbow Trout (Oncorhynchus mykiss)
Mingxian Chang,,Bertrand Collet, Pin Nie, Katherine Lester, Scott Campbell, Christopher J.
The retinoic acid-inducible gene I (RIG-I)-like receptors (RLR) comprise three homologues: RIG-I, melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2). They activate the host interferon (IFN) system upon recognition of viral RNA pathogen-associated molecular patterns (PAMPs) in the cytoplasm. Bioinformatic analysis of the sequenced vertebrate genomes suggests that the cytosolic surveillance system is conserved in lower vertebrates, and recent functional studies have confirmed that RIG-I is important to fish antiviral immunity. In this study, we have identified MDA5 and LGP2 homologues from rainbow trout Oncorhynchus mykiss and an additional LGP2 variant with an incomplete C-terminal domain of RIG-I. Trout MDA5 and LGP2 were constitutively produced in fibroblast and macrophage cell lines and upregulated by poly(I:C), recombinant IFN, or infection by RNA viruses (viral hemorrhagic septicemia virus and salmon alphavirus) with a single-stranded positive or negative genome. Overexpression of MDA5 and LGP2 but not of the LGP2 variant resulted in significant accumulation of Mx transcripts in cultured cells, which correlated with a marked enhancement of protection against viral infection. These results demonstrate that both MDA5 and LGP2 are important RLRs in host surveillance against infection of both negative and positive viruses and that the LGP2 variant with a deletion of 54 amino acids at the C terminus acts as a negative regulator for LGP2-elicited antiviral signaling by competing for the viral RNA PAMPs. Interestingly, MDA5 expression was not affected by overexpressed LGP2 in transfected cells and vice versa, suggesting that they likely act in parallel as positive regulators for IFN production.
