title: Tripartite motif-containing protein 38 negatively regulates TLR3/4- and RIG-I-mediated IFN-β production and antiviral response by targeting NAP1.
abstract: Recognition of RNA virus through TLR and RIG-I-like receptor results in rapid expression of type I IFNs, which play an essential role in host antiviral responses. However, the mechanisms to terminate the production of type I IFNs are not well defined. In the current study, we identified a member of the tripartite motif (TRIM) family, TRIM38, as a negative regulator in TLR3/4- and RIG-I-mediated IFN-β signaling. Knockdown of TRIM38 expression by small interfering RNA resulted in augmented activation of IFN regulatory factor 3 and enhanced expression of IFN-β, whereas overexpression of TRIM38 had opposite effects. Coimmunoprecipitation and colocalization experiments demonstrated that TRIM38 interacted with NF-κB-activating kinase-associated protein 1 (NAP1), which is required for TLR-induced IFN regulatory factor 3 activation and IFN-β production. As an E3 ligase, TRIM38 promoted K48-linked polyubiquitination and proteasomal degradation of NAP1. Thus, knockdown of TRIM38 expression resulted in higher protein level of NAP1 in primary macrophages. Consistent with the inhibitory roles in TLR3/4- and RIG-I-mediated IFN-β signaling, knockdown of TRIM38 significantly inhibited the replication of vesicular stomatitis virus. Overexpression of TRIM38 resulted in enhanced replication of vesicular stomatitis virus. Therefore, our results demonstrate that TRIM38 is a negative regulator for TLR and RIG-I-mediated IFN-β production by targeting NAP1 for ubiquitination and subsequent proteasome-mediated degradation.
authors.affiliation: Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, Shandong University Medical School, Jinan, Shandong, 250012, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wang
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Chao
authors.initials: C
authors.lastname: Yuan
authors.forename: Jianni
authors.initials: J
authors.lastname: Qi
authors.forename: Hong
authors.initials: H
authors.lastname: Meng
authors.forename: Chengjiang
authors.initials: C
authors.lastname: Gao
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors* / Q000502:physiology; D015536:Down-Regulation / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D016899:Interferon-beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination / Q000276:immunology; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology; D014779:Virus Replication / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C502089:Nckap1 protein, mouse; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D000070584:Tripartite Motif Proteins; D016899:Interferon-beta; C574194:TRIM38 protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases