RT Journal Article
SR Electronic
T1 Vesicular stomatitis virus transcription is inhibited by TRIM69 in the interferon-induced antiviral state
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 683292
DO 10.1101/683292
A1 Tonya Kueck
A1 Louis-Marie Bloyet
A1 Elena Cassella
A1 Trinity Zang
A1 Fabian Schmidt
A1 Vesna Brusic
A1 Gergely Tekes
A1 Owen Pornillos
A1 Sean P. J. Whelan
A1 Paul D. Bieniasz
YR 2019
UL http://biorxiv.org/content/early/2019/06/27/683292.abstract
AB 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 IFNα 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.SIGNIFICANCE STATEMENT Interferons are important antiviral cytokines that work by inducing hundreds of host genes whose products inhibit replication of many viruses. While the antiviral activity of interferon has long been known, the identities and mechanisms of action of most interferon-induced antiviral proteins remain to be discovered. We identified gene products that are important for the antiviral activity of interferon against vesicular stomatitis virus (VSV) a model virus that whose genome consists a single RNA molecule with negative sense polarity. We found that a particular antiviral protein, TRIM69, functions by a previously undescribed molecular mechanism. Specifically, TRIM69 interacts with, and inhibits the function, of a particular phosphoprotein (P) component the viral transcription machinery, preventing the synthesis of viral messenger RNAs.