NLRP12 Regulates Anti-viral RIG-I Activation via Interaction with TRIM25

Cell Host Microbe. 2019 Apr 10;25(4):602-616.e7. doi: 10.1016/j.chom.2019.02.013. Epub 2019 Mar 19.


Establishing the balance between positive and negative innate immune mechanisms is crucial for maintaining homeostasis. Here we uncover the regulatory crosstalk between two previously unlinked innate immune receptor families: RIG-I, an anti-viral cytosolic receptor activated type I interferon production, and NLR (nucleotide-binding domain, leucine repeat domain-containing protein). We show that NLRP12 dampens RIG-I-mediated immune signaling against RNA viruses by controlling RIG-I's association with its adaptor MAVS. The nucleotide-binding domain of NLRP12 interacts with the ubiquitin ligase TRIM25 to prevent TRIM25-mediated, Lys63-linked ubiquitination and activation of RIG-I. NLRP12 also enhances RNF125-mediated, Lys48-linked degradative ubiquitination of RIG-I. Vesicular stomatitis virus (VSV) infection downregulates NLRP12 expression to allow RIG-I activation. Myeloid-cell-specific Nlrp12-deficient mice display a heightened interferon and TNF response and are more resistant to VSV infection. These results indicate that NLRP12 functions as a checkpoint for anti-viral RIG-I activation.

Publication types

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

MeSH terms

  • Animals
  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / immunology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology*
  • Female
  • Humans
  • Interferons / genetics
  • Interferons / immunology
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein Binding
  • RNA Virus Infections / genetics
  • RNA Virus Infections / immunology*
  • RNA Virus Infections / virology
  • RNA Viruses / genetics
  • RNA Viruses / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / immunology*
  • Ubiquitination


  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • NLRP12 protein, mouse
  • Transcription Factors
  • Trim25 protein, mouse
  • Interferons
  • Ddx58 protein, mouse
  • DEAD Box Protein 58