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

• Published in: Cell host & microbe Vol. 25; no. 4; pp. 602 - 616.e7
• Main Authors: Chen, Szu-Ting, Chen, Liang, Lin, Diego Shih-Chieh, Chen, Sei-Yi, Tsao, Yen-Po, Guo, Haitao, Li, Fei-Ju, Tseng, Wei-Ting, Tam, Jason W., Chao, Chih-Wei, Brickey, W. June, Dzhagalov, Ivan, Song, Moon-Jung, Kang, Hye-Ri, Jung, Jae U., Ting, Jenny P.-Y.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.04.2019
• Subjects: 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
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2019.02.013

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. [Display omitted] •NLRP12 reduces interferon and cytokine responses to RNA viruses and 5′ppp-dsRNA•NLRP12 associates with TRIM25 to disrupt Lys63 ubiquitination and activation of RIG-I•Vesicular stomatitis virus (VSV) infection downregulates NLRP12•Myeloid-specific Nlrp12-deficient mice have increased resistance to VSV 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.