TRIM25 Enhances the Antiviral Action of Zinc-Finger Antiviral Protein (ZAP). Academic Article uri icon

Overview

abstract

  • The host factor and interferon (IFN)-stimulated gene (ISG) product, zinc-finger antiviral protein (ZAP), inhibits a number of diverse viruses by usurping and intersecting with multiple cellular pathways. To elucidate its antiviral mechanism, we perform a loss-of-function genome-wide RNAi screen to identify cellular cofactors required for ZAP antiviral activity against the prototype alphavirus, Sindbis virus (SINV). In order to exclude off-target effects, we carry out stringent confirmatory assays to verify the top hits. Important ZAP-liaising partners identified include proteins involved in membrane ion permeability, type I IFN signaling, and post-translational protein modification. The factor contributing most to the antiviral function of ZAP is TRIM25, an E3 ubiquitin and ISG15 ligase. We demonstrate here that TRIM25 interacts with ZAP through the SPRY domain, and TRIM25 mutants lacking the RING or coiled coil domain fail to stimulate ZAP's antiviral activity, suggesting that both TRIM25 ligase activity and its ability to form oligomers are critical for its cofactor function. TRIM25 increases the modification of both the short and long ZAP isoforms by K48- and K63-linked polyubiquitin, although ubiquitination of ZAP does not directly affect its antiviral activity. However, TRIM25 is critical for ZAP's ability to inhibit translation of the incoming SINV genome. Taken together, these data uncover TRIM25 as a bona fide ZAP cofactor that leads to increased ZAP modification enhancing its translational inhibition activity.

publication date

  • January 6, 2017

Research

keywords

  • Alphavirus Infections
  • Antiviral Agents
  • RNA-Binding Proteins
  • Sindbis Virus
  • Transcription Factors
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases

Identity

PubMed Central ID

  • PMC5245905

Scopus Document Identifier

  • 85010950545

Digital Object Identifier (DOI)

  • 10.1021/pr801109k

PubMed ID

  • 28060952

Additional Document Info

volume

  • 13

issue

  • 1