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

Huiyuan Zhang, Hongbo Hu, Nathaniel Greeley, Jin Jin, Allison J Matthews, Erika Ohashi, Mauricio S. Caetano, Haiyan S. Li, Xuefeng Wu, Pijus K. Mandal, John S. McMurray, Seyed Javad Moghaddam, Shao-Cong Sun and Stephanie S. Watowich ()
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Huiyuan Zhang: The University of Texas MD Anderson Cancer Center
Hongbo Hu: The University of Texas MD Anderson Cancer Center
Nathaniel Greeley: The University of Texas MD Anderson Cancer Center
Jin Jin: The University of Texas MD Anderson Cancer Center
Allison J Matthews: The University of Texas MD Anderson Cancer Center
Erika Ohashi: The University of Texas MD Anderson Cancer Center
Mauricio S. Caetano: The University of Texas MD Anderson Cancer Center
Haiyan S. Li: The University of Texas MD Anderson Cancer Center
Xuefeng Wu: The University of Texas MD Anderson Cancer Center
Pijus K. Mandal: The University of Texas MD Anderson Cancer Center
John S. McMurray: The University of Texas Graduate School of Biomedical Sciences
Seyed Javad Moghaddam: The University of Texas Graduate School of Biomedical Sciences
Shao-Cong Sun: The University of Texas MD Anderson Cancer Center
Stephanie S. Watowich: The University of Texas MD Anderson Cancer Center

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6798

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