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Nat Commun. 2014 Dec 15;5:5798. doi: 10.1038/ncomms6798.

STAT3 restrains RANK- and TLR4-mediated signalling by suppressing expression of the E2 ubiquitin-conjugating enzyme Ubc13.

Author information

1
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
2
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.
3
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
4
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
5
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.
6
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.

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.

PMID:
25503582
PMCID:
PMC4270087
DOI:
10.1038/ncomms6798
[Indexed for MEDLINE]
Free PMC Article

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