STAT3 restrains RANK- and TLR4-mediated signaling by suppressing expression of the E2 ubiquitin ligase Ubc13

• Published in: Nature communications Vol. 5; p. 5798
• Main Authors: Zhang, Huiyuan, Hu, Hongbo, Greeley, Nathaniel, Jin, Jin, Matthews, Allison J., Ohashi, Erika, Caetano, Mauricio S., Li, Haiyan S., Wu, Xuefeng, Mandal, Pijus K., McMurray, John S., Moghaddam, Seyed Javad, Sun, Shao-Cong, Watowich, Stephanie S.
• Format: Journal Article
• Language: English
• Published: 15.12.2014
• ISSN: 2041-1723
• DOI: 10.1038/ncomms6798

The transcriptional regulator STAT3 curbs pro-inflammatory cytokine production mediated by NF-κB signaling 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 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 this pathway plays important roles in bone homeostasis and restraint of inflammation.