UBXN1 Interferes With Rig-I-like Receptor-Mediated Antiviral Immune Response by Targeting MAVS

Cell Rep. 2013 Apr 25;3(4):1057-70. doi: 10.1016/j.celrep.2013.02.027. Epub 2013 Mar 28.

Abstract

RNA viruses are sensed by RIG-I-like receptors (RLRs), which signal through a mitochondria-associated adaptor molecule, MAVS, resulting in systemic antiviral immune responses. Although RLR signaling is essential for limiting RNA virus replication, it must be stringently controlled to prevent damage from inflammation. We demonstrate here that among all tested UBX-domain-containing protein family members, UBXN1 exhibits the strongest inhibitory effect on RNA-virus-induced type I interferon response. UBXN1 potently inhibits RLR- and MAVS-induced, but not TLR3-, TLR4-, or DNA-virus-induced innate immune responses. Depletion of UBXN1 enhances virus-induced innate immune responses, including those resulting from RNA viruses such as vesicular stomatitis, Sendai, West Nile, and dengue virus infection, repressing viral replication. Following viral infection, UBXN1 is induced, binds to MAVS, interferes with intracellular MAVS oligomerization, and disrupts the MAVS/TRAF3/TRAF6 signalosome. These findings underscore a critical role of UBXN1 in the modulation of a major antiviral signaling pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Antiviral Agents / pharmacology*
  • Cell Line, Tumor
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / metabolism
  • HEK293 Cells
  • Humans
  • Immunity, Innate / drug effects*
  • Interferon Type I / pharmacology*
  • Protein Binding
  • RNA Interference
  • RNA Viruses / immunology
  • RNA Viruses / physiology
  • RNA, Small Interfering / metabolism
  • Signal Transduction

Substances

  • Adaptor Proteins, Signal Transducing
  • Antiviral Agents
  • Interferon Type I
  • RNA, Small Interfering
  • UBXN1 protein, human
  • VISA protein, human
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases