Nicholas R Meyerson1, Ligang Zhou2, Yusong R Guo3, Chen Zhao2, Yizhi J Tao3, Robert M Krug4, Sara L Sawyer5. 1. BioFrontiers Institute, Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO 80303, USA. 2. Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, University of Texas at Austin, Austin, TX 78712, USA. 3. Department of BioSciences, Rice University, Houston, TX 77005, USA. 4. Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, University of Texas at Austin, Austin, TX 78712, USA. Electronic address: rkrug@austin.utexas.edu. 5. BioFrontiers Institute, Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO 80303, USA. Electronic address: ssawyer@colorado.edu.
Abstract
TRIM25 is an E3 ubiquitin ligase that activates RIG-I to promote the antiviral interferon response. The NS1 protein from all strains of influenza A virus binds TRIM25, although not all virus strains block the interferon response, suggesting alternative mechanisms for TRIM25 action. Here we present a nuclear role for TRIM25 in specifically restricting influenza A virus replication. TRIM25 inhibits viral RNA synthesis through a direct mechanism that is independent of its ubiquitin ligase activity and the interferon pathway. This activity can be inhibited by the viral NS1 protein. TRIM25 inhibition of viral RNA synthesis results from its binding to viral ribonucleoproteins (vRNPs), the structures containing individual viral RNA segments, the viral polymerase, and multiple viral nucleoproteins. TRIM25 binding does not inhibit initiation of capped-RNA-primed viral mRNA synthesis by the viral polymerase. Rather, the onset of RNA chain elongation is inhibited because TRIM25 prohibits the movement of RNA into the polymerase complex.
n class="Gene">TRIM25 is an E3 ubiquitin ligase that activates RIG-I to promote the antiviral interferon response. The NS1 protein from all strains of influenza A virus binds TRIM25, although not all virus strains block the interferon response, suggesting alternative mechanisms for TRIM25 action. Here we present a nuclear role for TRIM25 in specifically restricting influenza A virus replication. TRIM25 inhibits viral RNA synthesis through a direct mechanism that is independent of its ubiquitin ligase activity and the interferon pathway. This activity can be inhibited by the viral NS1 protein. TRIM25 inhibition of viral RNA synthesis results from its binding to viral ribonucleoproteins (vRNPs), the structures containing individual viral RNA segments, the viral polymerase, and multiple viral nucleoproteins. TRIM25 binding does not inhibit initiation of capped-RNA-primed viral mRNA synthesis by the viral polymerase. Rather, the onset of RNA chain elongation is inhibited because TRIM25 prohibits the movement of RNA into the polymerase complex.
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