title: The ubiquitin ligase TRAF6 negatively regulates the JAK-STAT signaling pathway by binding to STAT3 and mediating its ubiquitination.
abstract: STAT3 is a key transcription factor that mediates various cellular and organismal processes, such as cell growth, apoptosis, immune response and cancer. However, the molecular mechanisms of STAT3 regulation remain poorly understood. Here, we identified TRAF6 as a new STAT3 interactor. TRAF6 augmented the ubiquitination of STAT3 and deactivated its transcriptional activity induced by IFNα stimulation or overexpressed with JAK2. Both the RING domain and the TRAF-type zinc finger domain of TRAF6 were indispensable for STAT3 deactivation. Accordingly, TRAF6 also down-regulated the expression of two known STAT3 target genes, CRP and ACT. Therefore, we showed that TRAF6 is a new regulator of JAK/STAT signaling and provide a new mechanistic explanation for the crosstalk between the NF-κB and the JAK-STAT pathways.
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Juncheng
authors.initials: J
authors.lastname: Wei
authors.forename: Yanzhi
authors.initials: Y
authors.lastname: Yuan
authors.forename: Chaozhi
authors.initials: C
authors.lastname: Jin
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Ling
authors.initials: L
authors.lastname: Leng
authors.forename: Fuchu
authors.initials: F
authors.lastname: He
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation; D053612:Janus Kinases / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000737:chemistry*; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D048029:TNF Receptor-Associated Factor 6; D025801:Ubiquitin; D008156:Luciferases; D044767:Ubiquitin-Protein Ligases; D053612:Janus Kinases