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Vesicular stomatitis virus transcription is inhibited by TRIM69 in the interferon-induced antiviral state

By Tonya Kueck, Louis-Marie Bloyet, Elena Cassella, Trinity Zang, Fabian Schmidt, Vesna Brusic, Gergely Tekes, Owen Pornillos, Sean P. J. Whelan, Paul D D Bieniasz

Posted 27 Jun 2019
bioRxiv DOI: 10.1101/683292 (published DOI: 10.1128/JVI.01372-19)

Interferons (IFNs) induce the expression of many interferon stimulated genes (ISGs), many of which are responsible for the cellular antiviral state in which the replication of numerous viruses is blocked. How the majority of individual ISGs inhibit the replication of particular viruses is unknown. We conducted a loss-of-function screen to identify genes required for the activity of IFN against vesicular stomatitis virus, Indiana serotype (VSVIND), a prototype negative strand RNA virus. Our screen revealed that TRIM69, a member of tripartite motif family of proteins, is a VSVIND inhibitor. TRIM69 potently inhibited VSVIND replication through a previously undescribed transcriptional inhibition mechanism. Specifically, TRIM69 physically associates with the VSVIND phosphoprotein (P), requiring a specific peptide target sequence encoded therein. P is a cofactor for the viral polymerase, and is required for viral RNA synthesis as well as the assembly of replication compartments. By targeting P, TRIM69 inhibits pioneer transcription of the incoming virion-associated minus strand RNA, thereby preventing the synthesis of viral mRNAs, and consequently impedes all downstream events in the VSVIND replication cycle. Unlike some TRIM proteins, TRIM69 does not inhibit viral replication by inducing degradation of target viral proteins. Rather, higher-order TRIM69 multimerization is required for its antiviral activity, suggesting that TRIM69 functions by sequestration or anatomical disruption of the viral machinery required for VSVIND RNA synthesis.

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