哈獸研學者發現干擾素誘導的馬屬動物抗慢病毒感染的新機制

導讀

近日，中國農業科學院哈爾濱獸醫研究所馬傳染病與慢病毒病研究團隊在《Journal of Virology》在線發表了題為」Equine Myxovirus Resistance Protein 2 Restricts Lentiviral Replication by Blocking Nuclear Uptake of Capsid Protein」的研究論文。闡明了馬Myxovirus Resistance Protein 2（Mx2）蛋白對抗慢病毒感染的作用機制。

干擾素信號通路在馬屬動物對抗慢病毒感染中具有重要作用，其關鍵的分子機制尚不明確。該研究利用I型干擾素刺激馬外周血單核巨噬細胞,發現Mx2分子的表達可以被明顯上調。通過過表達和基因敲減技術，首次發現馬Mx2蛋白具有廣譜的慢病毒限制功能，可以明顯的限制靈長類慢病毒HIV-1、SIV，以及非靈長類慢病毒EIAV的複製，且該功能的發揮依賴於干擾素的誘導。該分子改變原有的胞質定位模式，通過聚集在細胞核周與感染病毒的衣殼蛋白結合，阻斷衣殼蛋白介導的病毒基因組的入核，從而發揮抗病毒功能。其N端缺失的突變體，由於不具有病毒衣殼蛋白的結合功能，因此喪失了限制病毒複製的能力。

先前的研究僅限於人源Mx2分子，其只能限制HIV-1等靈長類慢病毒的複製。而對其他非靈長類動物的逆轉錄病毒，如馬傳染性貧血病毒（EIAV），人的Mx2蛋白不具有限制作用。本研究證明了非靈長類動物的Mx2蛋白具有抵抗多種病毒的功能，提示該蛋白在物種天然免疫進化中扮演重要角色。這一發現豐富了對Mx2蛋白及其作用機制的認識。

該研究得到國家自然基金（81561128010和31222054）和獸醫生物技術國家重點實驗室基金的資助。王曉鈞研究員為文章的通訊作者,季爽博士為第一作者。

Abstract

Human Myxovirus resistance 2 (huMxB) has been shown to be a determinant type I interferon-induced host factor involved in the inhibition of HIV-1 as well as many other primate lentiviruses. This blocking occurs after the reverse transcription of viral RNA and ahead of the integration into the host DNA, which is closely connected to the ability of the protein to bind the viral capsid. To date, Mx2s derived from non-primate animals have shown no capacity for HIV-1 suppression. In this study, we examined the restrictive effect of equine Mx2 (eqMx2) on both the equine infectious anemia virus (EIAV) and HIV-1 and investigated possible mechanisms for its specific function. We demonstrated that IFNα/β upregulates the expression of eqMx2 in equine monocyte-derived macrophages (eMDMs). Overexpression of eqMx2 significantly suppresses the replication of EIAV, HIV-1, and SIVs, but not that of MLV. Knockdown of eqMx2 transcription weakens the inhibition of EIAV replication by type I interferon. Interestingly, immunofluorescence assays suggest that the subcellular localization of eqMx2 changes following virus infection, from being dispersed in the cytoplasm to being accumulated at the nuclear envelope. Furthermore, eqMx2 blocks the nuclear uptake of the proviral genome by binding to the viral capsid. The N-truncated mutant of eqMx2 lost the ability to bind the viral capsid as well as the restriction effect for lentiviruses. These results improve our understanding of the Mx2 protein in non-primate animals.IMPORTANCEPrevious research has shown that the antiviral ability of Mx2s is confined to primates, particularly humans. EIAV has been shown to be insensitive to the restriction by human MxB. Here, we described the function of equine Mx2. This protein plays an important role in the suppression of EIAV, HIV-1, and SIVs. The antiviral activity of eqMx2 depends on its subcellular location as well as its capsid binding capacity. Our results showed that following viral infection, eqMx2 changes its original cytoplasmic location and accumulates at the nuclear envelope where it binds to the viral capsid and blocks the nuclear entry of reverse transcribed proviral DNAs. In contrast, huMxB does not bind to the EIAV capsidand shows no EIAV restriction effect. These studies expand our understanding of the function of the equine Mx2 protein.

本文來源：中國農業科學院哈爾濱獸醫研究所

本期編輯：rojjer

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