TRIM5alpha藉由促進Rta的泛素化緩解Epstein-Barr virus的溶裂循環

Abstract

極早期蛋白質Rta是促進Epstein-Barr virus (EBV) 進入溶裂循環時很重要的轉錄因子。Tripartite-motif 5 alpha (TRIM5alpha) 是反轉錄病毒限制因子 (restriction factor)，具有泛素E3連接酶 (ubiquitin E3 ligase) 的活性，在特定靈長類中能保護宿主免於反轉錄病毒 (retrovirus) 的侵害。然而，目前報導中，TRIM5alpha的限制目標大都限於反轉錄病毒，而鮮少有DNA病毒。本研究發現人類的TRIM5alpha能與Rta在細胞質直接結合。兩者的交互作用透過Rta的N端序列與TRIM5alpha C端的B30.2功能區而發生。另外，TRIM5alpha會促進Rta的泛素化，若過量表現TRIM5alpha也會導致Rta的濃度降低及下游的轉錄活化遭到抑制，進而緩解EBV的溶裂循環。綜合以上，本研究第一個發現人類TRIM5alpha作用於DNA病毒的蛋白質上，透過與Rta的結合並促進其泛素化，使EBV的溶裂循環受到抑制。

An immediate-early protein, Rta, is an important transcription factor required for initiating the lytic cycle of Epstein-Barr virus (EBV). Tripartite-motif 5 alpha (TRIM5alpha) is a restriction factor of retroviruses with the ubiquitin E3 ligase activity, which protects primates form retrovirus infection in a species-specific manner. However, the documented target spectrum of TRIM5alpha was limited to RNA viruses. This study finds that TRIM5alpha is a binding partner of Rta and colocalizes with Rta in the cytoplasm. The interaction involves the N-terminal region in Rta and the C-terminal B30.2 domain in TRIM5alpha. Moreover, overexpression of TRIM5alpha facilitates the ubiquitination of Rta and reduces the level of Rta, thereby inhibiting the transactivation activity of Rta. Collectively, this study identifies Rta to be the first DNA viral target of human TRIM5alpha, and the interaction prevents EBV lytic progression by promoting Rta's ubiquitination.