title: STAT3 restrains RANK- and TLR4-mediated signalling by suppressing expression of the E2 ubiquitin-conjugating enzyme Ubc13.
abstract: The transcriptional regulator STAT3 curbs pro-inflammatory cytokine production mediated by NF-κB signalling in innate immune cells, yet the mechanism by which this occurs has been unclear. Here we identify STAT3 as a pivotal negative regulator of Ubc13, an E2 ubiquitin-conjugating enzyme that facilitates TRAF6 K63-linked ubiquitination and NF-κB activation. Ubc13 accumulates intracellularly in the absence of STAT3. Depletion of Ubc13 in Stat3-deficient macrophages subdues excessive RANKL- or LPS-dependent gene expression, indicating that Ubc13 overexpression mediates enhanced transcriptional responses in the absence of STAT3. In RANKL-activated macrophages, STAT3 is stimulated by autocrine IL-6 and inhibits accrual of Ets-1, Set1 methyltransferase and trimethylation of histone H3 lysine 4 (H3K4me3) at the Ube2n (Ubc13) promoter. These results delineate a mechanism by which STAT3 operates as a transcriptional repressor on Ube2n, thus modulating NF-κB activity by regulation of Ubc13 abundance. Our data suggest that this pathway plays important roles in bone homeostasis and restraint of inflammation.
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Hu
authors.affiliation: 1] Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Greeley
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Matthews
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Ohashi
authors.affiliation: Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Mauricio S
authors.initials: MS
authors.lastname: Caetano
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Haiyan S
authors.initials: HS
authors.lastname: Li
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Pijus K
authors.initials: PK
authors.lastname: Mandal
authors.affiliation: 1] The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA [2] Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: McMurray
authors.affiliation: 1] The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA [2] Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Seyed Javad
authors.initials: SJ
authors.lastname: Moghaddam
authors.affiliation: 1] Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA.
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
authors.affiliation: 1] Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Watowich
mesh_terms: D000818:Animals; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D050784:Proto-Oncogene Protein c-ets-1; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C494042:Ets1 protein, mouse; D006657:Histones; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050784:Proto-Oncogene Protein c-ets-1; D053245:RANK Ligand; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D048029:TNF Receptor-Associated Factor 6; C493487:Tlr4 protein, mouse; C505689:Tnfsf11 protein, mouse; D051197:Toll-Like Receptor 4; D011495:Histone-Lysine N-Methyltransferase; C514982:Ube2n protein, mouse; D044763:Ubiquitin-Conjugating Enzymes