NAC1 Potentiates Cellular Antiviral Signaling by Bridging MAVS and TBK1

J Immunol. 2019 Aug 15;203(4):1001-1011. doi: 10.4049/jimmunol.1801110. Epub 2019 Jun 24.

Abstract

Intracellular viral RNAs are recognized by the RIG-I-like receptors (RLRs), which signal through the mitochondrial antiviral signaling protein MAVS. MAVS recruits and activates TBK1 kinase, which further phosphorylates and activates the transcription factor IRF3, leading to the induction of type I IFN and downstream antiviral genes. We identified human nucleus accumbens-associated 1 (NAC1), a member of the BTB/POZ family, as a bridge for MAVS and TBK1 that positively regulates the RLR-mediated induction of type I IFN. Overexpression or knockdown of NAC1 could, respectively, enhance or impair Sendai virus-triggered activation of TBK1 and IRF3, as well as induction of IFN-β. NAC1 also significantly boosted host antiviral responses against multiple RNA viruses. NAC1 was able to interact with MAVS and TBK1 upon viral infection. The BTB/POZ domain (aa 1-133) of NAC1 interacted with MAVS, and the remainder of NAC1 bound to TBK1. Furthermore, NAC1 could promote the recruitment of TBK1 to MAVS. In contrast, knockdown of NAC1 attenuated the interaction between TBK1 and MAVS. Collectively, our study characterizes NAC1 as an important component of RLR-mediated innate immune responses and uncovers a previously unrecognized function of the BTB/POZ family proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / immunology*
  • Cell Line
  • Humans
  • Immunity, Innate / immunology
  • Neoplasm Proteins / immunology*
  • Protein Serine-Threonine Kinases / immunology*
  • RNA Virus Infections / immunology*
  • RNA Viruses / immunology
  • Repressor Proteins / immunology*
  • Signal Transduction / immunology*

Substances

  • Adaptor Proteins, Signal Transducing
  • MAVS protein, human
  • NACC1 protein, human
  • Neoplasm Proteins
  • Repressor Proteins
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human