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

Szu Ting Chen, Liang Chen, Diego Shih Chieh Lin, Sei Yi Chen, Yen Po Tsao, Haitao Guo, Fei Ju Li, Wei Ting Tseng, Jason W. Tam, Chih Wei Chao, W. June Brickey, Ivan Dzhagalov, Moon Jung Song, Hye Ri Kang, Jae U. Jung, Jenny P.Y. Ting

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

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. Chen et al. show that the nucleotide-binding domain and leucine repeat domain-containing protein NLRP12 associates with the ubiquitin ligase TRIM25 to reduce K63-linked ubiquitination of the anti-viral innate immune receptor RIG-I. This prevents RIG-I association with MAVS and thus serves as a checkpoint for interferon and cytokine induction in response to RNA viruses.

Original languageEnglish
Pages (from-to)602-616.e7
JournalCell Host and Microbe
Volume25
Issue number4
DOIs
Publication statusPublished - 2019 Apr 10

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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