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

59 Citations (Scopus)


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
Issue number4
Publication statusPublished - 2019 Apr 10

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health , United States U19-AI109965 , DK094779 , CA156330 and AI029564 (J.P.-Y.T.); National Science Council , Taiwan NSC 103-2320-B-038-004-MY2 ; Ministry of Science and Technology , Taiwan MOST 104-2320-B-010-0440-MY3 ; National Yang-Ming University School of Medicine of Development and Construction program 107F-MOI; and the Cancer Progression Research Center, National Yang-Ming University, from the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. We thank the following for core and technical support: National Yang-Ming University Imaging Core Facility, Flow Cytometry Core Facility, Animal Studies Core Facility and Taiwan Animal Consortium, Taiwan Mouse Clinic, UNC Animal Models Core, Animal Histopathology Core Facility, and Animal Studies Core Facility. We thank Dr. S.-L.H. for providing critical reagents.

Publisher Copyright:
© 2019 Elsevier Inc.

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology


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