Analyses of the mechanism of virus budding

最近的研究表明，许多包膜病毒的Gag或基质蛋白，包括逆转录病毒、横纹病毒、ARENA病毒和丝状病毒，都含有一个所谓的L结构域，其中包含PPxY、PT/SAP或YPxL，它们是有效萌发的关键基序。PPxY、PT/SAP或YPxL基序分别与细胞内Nedd4样泛素连接酶Tsg101或AIP1/Alix相互作用。这些宿主因子参与了E类空泡蛋白分选(VPS)途径，表明病毒在质膜上发芽和发芽进入多泡小体(MVB)的管腔在拓扑上是相同的，并且具有共同的机制。在本研究中，为了阐明HTLV-1、M-PMV、LASA和流感病毒的萌发机制，并开发新的抗病毒策略，我们分析了病毒和细胞对病毒萌发的要求。1、流感病毒需要病毒M1、HA、NA和NP蛋白来有效地萌发VLP。2、LASA病毒Z蛋白足以释放病毒样颗粒，并具有PPPY作为功能结构域。3、LASA病毒在萌发过程中使用细胞因子Vps4A、Vps4B和Tsg101。4、Lassa病毒萌发通过MVB途径发挥作用虽然M-PMV和HTLV-1都含有PPxY和PT/SAP序列，但在两种病毒中，PPxY序列而不是PSAP序列主要作为病毒的L结构域发挥作用。5、Tsg101以不依赖于PSAP的方式参与M-PMV的发芽。6、AIP1/Alix和Vps4A/B也参与了M-PMV的发芽，表明M-PMV的发芽利用了细胞多泡体的分选途径。

Recent studies have revealed that the Gag or matrix proteins of many enveloped RNA viruses including retro-, rhabdo-, arena-, and filoviruses possess a so-called L-domain containing PPxY, PT/SAP, or YPxL, which are critical motifs for efficient budding. PPxY, PT/SAP, or YPxL motifs interact with cellular Nedd4-like ubiquitin ligases, Tsg101, or AIP1/ALIX, respectively. These host factors are involved in class E vacuolar protein-sorting (VPS) pathway, suggesting that the budding into the lumen of multivesicular bodies (MVBs) and viral budding at plasma membrane are topologically identical and share a common mechanism. In this study, to clarify the mechanism of budding of HTLV-1, M-PMV, Lassa and Influenza viruses and develop novel anti-viral strategies, we analyzed viral and cellular requirements for virus budding.The followings are results from my studies.1, Influenza virus requires viral M1, HA, NA and NP proteins for efficient VLP budding.2, Lassa virus Z protein is sufficient for the release of virus like particle (VLP) and has PPPY as a functional L-domain.3, Lassa virus uses cellular factors, Vps4A, Vps4B and Tsg101 in its budding, suggesting that Lassa virus budding uses MVB pathway functionally.4, Although M-PMV and HTLV- 1 contains both PPxY and PT/SAP sequences, the PPxY sequence, but not the PSAP sequence, mainly functions as the viral L-domain in both viruses.5, Tsg101 is involved in M-PMV budding in a PSAP-independent manner.6, AIP 1/Alix and Vps4A/B are also involved in M-PMV budding, suggesting that M-PMV budding utilizes the cellular multivesicular body (MVB) sorting pathway.7, PSAP motif plays an important role in earlier steps of M-PMV replication, but not in virus budding.