The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA.
Viral infection activates transcription factors NF-kappaB and IRF3, which collaborate to induce type I interferons (IFNs) and elicit innate antiviral response. MITA (also known as STING) has recently been identified as an adaptor that links virus-sensing receptors to IRF3 activation. Here, we showed that the E3 ubiquitin ligase RNF5 interacted with MITA in a viral-infection-dependent manner. Overexpression of RNF5 inhibited virus-triggered IRF3 activation, IFNB1 expression, and cellular antiviral response, whereas knockdown of RNF5 had opposite effects. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection. Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) and viral infection caused their redistribution to the ER and mitochondria, respectively. We further found that virus-induced ubiquitination and degradation of MITA by RNF5 occurred at the mitochondria. These findings suggest that RNF5 negatively regulates virus-triggered signaling by targeting MITA for ubiquitination and degradation at the mitochondria.
Zhong
Bo
B
College of Life Sciences, Wuhan University, Wuhan 430072, China.
Zhang
Lu
L
Lei
Caoqi
C
Li
Ying
Y
Mao
Ai-Ping
AP
Yang
Yan
Y
Wang
Yan-Yi
YY
Zhang
Xiao-Lian
XL
Shu
Hong-Bing
HB
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation; D014777:Virus Diseases / Q000276:immunology*; D014780:Viruses / Q000276:immunology; D000099197:STING Protein
D033942:Adaptor Proteins, Vesicular Transport; D004268:DNA-Binding Proteins; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016899:Interferon-beta; D008565:Membrane Proteins; D016328:NF-kappa B; D044767:Ubiquitin-Protein Ligases; C532857:STING1 protein, human; D000099197:STING Protein; C111501:RNF5 protein, human