Department of Chemistry University of Michigan, Ann Arbor, Michigan-48109 United States.
J Am Chem Soc. 2021 Apr 7;143(13):4910-4914. doi: 10.1021/jacs.1c01045. Epub 2021 Mar 29.
Viperin is a broadly conserved radical SAM enzyme that synthesizes the antiviral nucleotide ddhCTP. In higher animals, viperin expression also accelerates the degradation of various cellular and viral proteins necessary for viral replication; however, the details of this process remain largely unknown. Here, we show that viperin activates a component of the protein ubiquitination machinery, which plays an important role in both protein degradation and immune signaling pathways. We demonstrate that viperin binds the E3 ubiquitin ligase, TRAF6, which catalyzes K63-linked ubiquitination associated with immune signaling pathways. Viperin activates ubiquitin transfer by TRAF6-2.5-fold and causes a significant increase in polyubiquitinated forms of TRAF6 that are important for mediating signal transduction. Our observations both imply a role for viperin as an agonist of immune signaling and suggest that viperin may activate other K48-linked E3-ligases involved in targeting proteins for proteasomal degradation.
Viperin 是一种广泛保守的自由基 SAM 酶，可合成抗病毒核苷酸 ddhCTP。在高等动物中，Viperin 的表达也加速了各种细胞和病毒复制所需的病毒蛋白的降解；然而，这个过程的细节在很大程度上仍然未知。在这里，我们表明 Viperin 激活了蛋白质泛素化机制的一个组成部分，该机制在蛋白质降解和免疫信号通路中都起着重要作用。我们证明 Viperin 结合了 E3 泛素连接酶 TRAF6，该酶催化与免疫信号通路相关的 K63 连接泛素化。Viperin 将 TRAF6 的泛素转移活性激活了 2.5 倍，并导致 TRAF6 的多聚泛素化形式显著增加，这对于介导信号转导很重要。我们的观察结果既暗示了 Viperin 作为免疫信号激动剂的作用，也表明 Viperin 可能激活其他涉及靶向蛋白质进行蛋白酶体降解的 K48 连接 E3 连接酶。
