Cargando…

THO Complex Subunit 7 Homolog Negatively Regulates Cellular Antiviral Response against RNA Viruses by Targeting TBK1

RNA virus invasion induces a cytosolic RIG-I-like receptor (RLR) signaling pathway by promoting assembly of the Mitochondrial antiviral-signaling protein (MAVS) signalosome and triggers the rapid production of type I interferons (IFNs) and proinflammatory cytokines. During this process, the pivotal...

Descripción completa

Detalles Bibliográficos
Autores principales: He, Tian-Sheng, Xie, Tao, Li, Jing, Yang, Ya-Xian, Li, Changsheng, Wang, Weiying, Cao, Lingzhen, Rao, Hua, Ju, Cynthia, Xu, Liang-Guo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410154/
https://www.ncbi.nlm.nih.gov/pubmed/30769920
http://dx.doi.org/10.3390/v11020158
_version_ 1783402173938270208
author He, Tian-Sheng
Xie, Tao
Li, Jing
Yang, Ya-Xian
Li, Changsheng
Wang, Weiying
Cao, Lingzhen
Rao, Hua
Ju, Cynthia
Xu, Liang-Guo
author_facet He, Tian-Sheng
Xie, Tao
Li, Jing
Yang, Ya-Xian
Li, Changsheng
Wang, Weiying
Cao, Lingzhen
Rao, Hua
Ju, Cynthia
Xu, Liang-Guo
author_sort He, Tian-Sheng
collection PubMed
description RNA virus invasion induces a cytosolic RIG-I-like receptor (RLR) signaling pathway by promoting assembly of the Mitochondrial antiviral-signaling protein (MAVS) signalosome and triggers the rapid production of type I interferons (IFNs) and proinflammatory cytokines. During this process, the pivotal kinase TANK binding kinase 1 (TBK1) is recruited to the MAVS signalosome to transduce a robust innate antiviral immune response by phosphorylating transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor (NF)-κB and promoting their nuclear translocation. However, the molecular mechanisms underlying the negative regulation of TBK1 are largely unknown. In the present study, we found that THO complex subunit 7 homolog (THOC7) negatively regulated the cellular antiviral response by promoting the proteasomal degradation of TBK1. THOC7 overexpression potently inhibited Sendai virus- or polyI:C-induced IRF3 dimerization and phosphorylation and IFN-β production. In contrast, THOC7 knockdown had the opposite effects. Moreover, we simulated a node-activated pathway to show that THOC7 regulated the RIG-I-like receptors (RLR)-/MAVS-dependent signaling cascade at the TBK1 level. Furthermore, THOC7 was involved in the MAVS signalosome and promoted TBK1 degradation by increasing its K48 ubiquitin-associated polyubiquitination. Together, these findings suggest that THOC7 negatively regulates type I IFN production by promoting TBK1 proteasomal degradation, thus improving our understanding of innate antiviral immune responses.
format Online
Article
Text
id pubmed-6410154
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-64101542019-04-01 THO Complex Subunit 7 Homolog Negatively Regulates Cellular Antiviral Response against RNA Viruses by Targeting TBK1 He, Tian-Sheng Xie, Tao Li, Jing Yang, Ya-Xian Li, Changsheng Wang, Weiying Cao, Lingzhen Rao, Hua Ju, Cynthia Xu, Liang-Guo Viruses Article RNA virus invasion induces a cytosolic RIG-I-like receptor (RLR) signaling pathway by promoting assembly of the Mitochondrial antiviral-signaling protein (MAVS) signalosome and triggers the rapid production of type I interferons (IFNs) and proinflammatory cytokines. During this process, the pivotal kinase TANK binding kinase 1 (TBK1) is recruited to the MAVS signalosome to transduce a robust innate antiviral immune response by phosphorylating transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor (NF)-κB and promoting their nuclear translocation. However, the molecular mechanisms underlying the negative regulation of TBK1 are largely unknown. In the present study, we found that THO complex subunit 7 homolog (THOC7) negatively regulated the cellular antiviral response by promoting the proteasomal degradation of TBK1. THOC7 overexpression potently inhibited Sendai virus- or polyI:C-induced IRF3 dimerization and phosphorylation and IFN-β production. In contrast, THOC7 knockdown had the opposite effects. Moreover, we simulated a node-activated pathway to show that THOC7 regulated the RIG-I-like receptors (RLR)-/MAVS-dependent signaling cascade at the TBK1 level. Furthermore, THOC7 was involved in the MAVS signalosome and promoted TBK1 degradation by increasing its K48 ubiquitin-associated polyubiquitination. Together, these findings suggest that THOC7 negatively regulates type I IFN production by promoting TBK1 proteasomal degradation, thus improving our understanding of innate antiviral immune responses. MDPI 2019-02-15 /pmc/articles/PMC6410154/ /pubmed/30769920 http://dx.doi.org/10.3390/v11020158 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
He, Tian-Sheng
Xie, Tao
Li, Jing
Yang, Ya-Xian
Li, Changsheng
Wang, Weiying
Cao, Lingzhen
Rao, Hua
Ju, Cynthia
Xu, Liang-Guo
THO Complex Subunit 7 Homolog Negatively Regulates Cellular Antiviral Response against RNA Viruses by Targeting TBK1
title THO Complex Subunit 7 Homolog Negatively Regulates Cellular Antiviral Response against RNA Viruses by Targeting TBK1
title_full THO Complex Subunit 7 Homolog Negatively Regulates Cellular Antiviral Response against RNA Viruses by Targeting TBK1
title_fullStr THO Complex Subunit 7 Homolog Negatively Regulates Cellular Antiviral Response against RNA Viruses by Targeting TBK1
title_full_unstemmed THO Complex Subunit 7 Homolog Negatively Regulates Cellular Antiviral Response against RNA Viruses by Targeting TBK1
title_short THO Complex Subunit 7 Homolog Negatively Regulates Cellular Antiviral Response against RNA Viruses by Targeting TBK1
title_sort tho complex subunit 7 homolog negatively regulates cellular antiviral response against rna viruses by targeting tbk1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410154/
https://www.ncbi.nlm.nih.gov/pubmed/30769920
http://dx.doi.org/10.3390/v11020158
work_keys_str_mv AT hetiansheng thocomplexsubunit7homolognegativelyregulatescellularantiviralresponseagainstrnavirusesbytargetingtbk1
AT xietao thocomplexsubunit7homolognegativelyregulatescellularantiviralresponseagainstrnavirusesbytargetingtbk1
AT lijing thocomplexsubunit7homolognegativelyregulatescellularantiviralresponseagainstrnavirusesbytargetingtbk1
AT yangyaxian thocomplexsubunit7homolognegativelyregulatescellularantiviralresponseagainstrnavirusesbytargetingtbk1
AT lichangsheng thocomplexsubunit7homolognegativelyregulatescellularantiviralresponseagainstrnavirusesbytargetingtbk1
AT wangweiying thocomplexsubunit7homolognegativelyregulatescellularantiviralresponseagainstrnavirusesbytargetingtbk1
AT caolingzhen thocomplexsubunit7homolognegativelyregulatescellularantiviralresponseagainstrnavirusesbytargetingtbk1
AT raohua thocomplexsubunit7homolognegativelyregulatescellularantiviralresponseagainstrnavirusesbytargetingtbk1
AT jucynthia thocomplexsubunit7homolognegativelyregulatescellularantiviralresponseagainstrnavirusesbytargetingtbk1
AT xuliangguo thocomplexsubunit7homolognegativelyregulatescellularantiviralresponseagainstrnavirusesbytargetingtbk1