2. Academic Validation
  3. NLRP12 Regulates Anti-viral RIG-I Activation via Interaction with TRIM25

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.
Szu-Ting Chen 1,  Liang Chen 2,  Diego Shih-Chieh Lin 3,  Sei-Yi Chen 4,  Yen-Po Tsao 5,  Haitao Guo 6,  Fei-Ju Li 7,  Wei-Ting Tseng 7,  Jason W Tam 6,  Chih-Wei Chao 7,  W June Brickey 2,  Ivan Dzhagalov 8,  Moon-Jung Song 9,  Hye-Ri Kang 9,  Jae U Jung 10,  Jenny P-Y Ting 11
Affiliations

Affiliations

  • 1 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Cancer Progression Research Center, National Yang-Ming University, Taipei, Taiwan; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. Electronic address: [email protected].
  • 2 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA.
  • 3 Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
  • 4 Department of Neurosurgery, Chung-Shan Medical University Hospital, Taichung, Taiwan; School of Medicine, Chung-Shan Medical University, Taichung, Taiwan.
  • 5 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
  • 6 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
  • 7 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
  • 8 Department of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
  • 9 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Virus-Host Interactions Laboratory, Department of Biosystems and Biotechnology, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
  • 10 Department of Molecular Microbiology & Immunology, University of Southern California Keck School of Medicine, CA, USA.
  • 11 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA; Institute of Inflammatory Diseases, Center for Translational Immunology, University of North Carolina, Chapel Hill, NC, USA. Electronic address: [email protected].
PMID: 30902577 DOI: 10.1016/j.chom.2019.02.013
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.

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