title: Ndfip1 negatively regulates RIG-I-dependent immune signaling by enhancing E3 ligase Smurf1-mediated MAVS degradation.
abstract: Ndfip1 functions as both a recruiter and an activator of multiple HECT domain E3 ubiquitin ligases of the Nedd4 family. In this study, we demonstrate that Ndfip1 is involved in the ubiquitin-mediated degradation of mitochondrial antiviral signaling (MAVS), which is a key adaptor protein in RIG-I-like receptor-mediated immune signaling. We found that overexpression of Ndfip1 severely impaired MAVS and Sendai virus-mediated activation of IFN-stimulated response element, NF-κB, IFN-β promoter, and polyinosinic-polycytidylic acid or influenza virus RNA-stimulated IRF-3 phosphorylation, as well as the transcription of IFN-β. This functional interaction was confirmed by knockdown of Ndfip1, which facilitated MAVS-mediated downstream signaling and elevated MAVS protein levels. Further analysis indicated that Ndfip1 enhances both self-ubiquitination of HECT domain-containing E3 ubiquitin ligase Smurf1 and its interaction with MAVS, and eventually promotes MAVS degradation. In addition, the activation of IFN-β by MAVS, influenza virus RNA, polyinosinic-polycytidylic acid, and Sendai virus was enhanced in Ndfip1 knockdown cells. These results reveal that Ndfip1 is a potent inhibitor of MAVS-mediated antiviral response.
authors.affiliation: Center for Molecular Immunology, Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yetao
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Tong
authors.forename: Xin
authors.initials: X
authors.lastname: Ye
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D059748:Proteolysis / Q000187:drug effects; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D011971:Receptors, Immunologic; D029082:Sendai virus / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D025801:Ubiquitin / Q000235:genetics / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C505371:MAVS protein, human; D008565:Membrane Proteins; C451223:NDFIP1 protein, human; D016328:NF-kappa B; D012367:RNA, Viral; D011971:Receptors, Immunologic; D025801:Ubiquitin; D016899:Interferon-beta; D007371:Interferon-gamma; C498342:SMURF1 protein, human; D044767:Ubiquitin-Protein Ligases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D011070:Poly I-C