Schmidt Hannah M, Sorensen Grace C, Lanahan Matthew R, Grabowski Jenna, Park Moonhee, Horner Stacy M
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA.
Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA.
bioRxiv. 2025 Jan 9:2025.01.09.632082. doi: 10.1101/2025.01.09.632082.
Post-translational modifications play crucial roles in viral infections, yet many potential modifications remain unexplored in orthoflavivirus biology. Here we demonstrate that the UFMylation system, a post-translational modification system that catalyzes the transfer of UFM1 onto proteins, promotes infection by multiple orthoflaviviruses including dengue virus, Zika virus, West Nile virus, and yellow fever virus. We found that depletion of the UFMylation E3 ligase complex proteins UFL1 and UFBP1, as well as other UFMylation machinery components (UBA5, UFC1, and UFM1), significantly reduces infectious virion production for orthoflaviviruses but not the hepacivirus, hepatitis C. Mechanistically, UFMylation does not regulate viral RNA translation or RNA replication but instead affects a later stage of the viral lifecycle. We identified novel interactions between UFL1, and several viral proteins involved in orthoflavivirus virion assembly, including NS2A, NS2B-NS3, and Capsid. These findings establish UFMylation as a previously unrecognized post-translational modification system that promotes orthoflavivirus infection, likely through modulation of viral assembly. This work expands our understanding of the post-translational modifications that control orthoflavivirus infection and identifies new potential therapeutic targets.
翻译后修饰在病毒感染中起着关键作用，但在正黄病毒生物学中，许多潜在的修饰仍未被探索。在此，我们证明了UFMylation系统，一种催化UFM1转移到蛋白质上的翻译后修饰系统，能促进包括登革病毒、寨卡病毒、西尼罗河病毒和黄热病毒在内的多种正黄病毒的感染。我们发现，UFMylation E3连接酶复合物蛋白UFL1和UFBP1以及其他UFMylation机制组件（UBA5、UFC1和UFM1）的缺失，会显著降低正黄病毒感染性病毒粒子的产生，但不会影响丙型肝炎病毒的产生。从机制上讲，UFMylation并不调节病毒RNA翻译或RNA复制，而是影响病毒生命周期的后期阶段。我们确定了UFL1与几种参与正黄病毒病毒粒子组装的病毒蛋白之间的新相互作用，包括NS2A、NS2B-NS3和衣壳蛋白。这些发现确立了UFMylation是一种以前未被认识的翻译后修饰系统，它可能通过调节病毒组装来促进正黄病毒感染。这项工作扩展了我们对控制正黄病毒感染的翻译后修饰的理解，并确定了新的潜在治疗靶点。
