Error message

No crossref credentials set for sci

Negative Regulation of Toll-Like Receptor Signaling by NF-κB p50 Ubiquitination Blockade

Science, 3 August 2007
Vol. 317, Issue 5838, p. 675-678
DOI: 10.1126/science.1142953

Negative Regulation of Toll-Like Receptor Signaling by NF-κB p50 Ubiquitination Blockade

  1. Ruaidhrí J. Carmody,
  2. Qingguo Ruan,
  3. Scott Palmer,
  4. Brendan Hilliard,
  5. Youhai H. Chen*
  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
  1. * To whom correspondence should be addressed. E-mail: yhc{at}


Toll-like receptors (TLRs) trigger the production of inflammatory cytokines and shape adaptive and innate immunity to pathogens. We report the identification of B cell leukemia (Bcl)–3 as an essential negative regulator of TLR signaling. By blocking ubiquitination of p50, a member of the nuclear factor (NF)-κB family, Bcl-3 stabilizes a p50 complex that inhibits gene transcription. As a consequence, Bcl-3–deficient mice and cells were found to be hypersensitive to TLR activation and unable to control responses to lipopolysaccharides. Thus, p50 ubiquitination blockade by Bcl-3 limits the strength of TLR responses and maintains innate immune homeostasis. These findings indicate that the p50 ubiquitination pathway can be selectively targeted to control deleterious inflammatory diseases.

  • Received for publication 23 March 2007.
  • Accepted for publication 27 June 2007.


R. J. Carmody, Q. Ruan, S. Palmer, B. Hilliard, and Y. H. Chen, Negative Regulation of Toll-Like Receptor Signaling by NF-κB p50 Ubiquitination Blockade. Science 317, 675-678 (2007).

BTB-ZF transcriptional regulator PLZF modifies chromatin to restrain inflammatory signaling programs
A. J. Sadler, F. J. Rossello, L. Yu, J. A. Deane, X. Yuan, D. Wang, A. T. Irving, M. Kaparakis-Liaskos, M. P. Gantier, H. Ying et al.
Proc. Natl. Acad. Sci. USA 112, 1535-1540 (3 February 2015)

Batf3-independent langerin- CX3CR1- CD8{alpha}+ splenic DCs represent a precursor for classical cross-presenting CD8{alpha}+ DCs
T. R. Petersen, D. A. Knight, C.-W. Tang, T. L. Osmond, and I. F. Hermans
J. Leukoc. Biol. 96, 1001-1010 (1 December 2014)

The NF-{kappa}B Regulator Bcl-3 Governs Dendritic Cell Antigen Presentation Functions in Adaptive Immunity
I. Tassi, E. Claudio, H. Wang, W. Tang, H.-l. Ha, S. Saret, M. Ramaswamy, R. Siegel, and U. Siebenlist
J. Immunol. 193, 4303-4311 (1 November 2014)

Moderate Alcohol Induces Stress Proteins HSF1 and hsp70 and Inhibits Proinflammatory Cytokines Resulting in Endotoxin Tolerance
S. Muralidharan, A. Ambade, M. A. Fulham, J. Deshpande, D. Catalano, and P. Mandrekar
J. Immunol. 193, 1975-1987 (15 August 2014)

InnateDB: facilitating systems-level analyses of the mammalian innate immune response
D. J. Lynn, G. L. Winsor, C. Chan, N. Richard, M. R. Laird, A. Barsky, J. L. Gardy, F. M. Roche, T. H. W. Chan, N. Shah et al.
Mol Syst Biol 4, 218-218 (28 July 2014)

Inhibition of Transcription by B Cell Leukemia 3 (Bcl-3) Protein Requires Interaction with Nuclear Factor {kappa}B (NF-{kappa}B) p50
P. E. Collins, P. A. Kiely, and R. J. Carmody
J Biol Chem 289, 7059-7067 (7 March 2014)

Identification of a Unique Hybrid Macrophage-Polarization State following Recovery from Lipopolysaccharide Tolerance
C. O'Carroll, A. Fagan, F. Shanahan, and R. J. Carmody
J. Immunol. 192, 427-436 (1 January 2014)

The Tumor Promoter and NF-{kappa}B Modulator Bcl-3 Regulates Splenic B Cell Development
X. Zhang, A. Paun, E. Claudio, H. Wang, and U. Siebenlist
J. Immunol. 191, 5984-5992 (15 December 2013)

A mechanistic study of the proapoptotic effect of tolfenamic acid: involvement of NF-{kappa}B activation
J. B. Jeong, X. Yang, R. Clark, J. Choi, S. J. Baek, and S.-H. Lee
Carcinogenesis 34, 2350-2360 (1 October 2013)

Dissociation of Endotoxin Tolerance and Differentiation of Alternatively Activated Macrophages
R. Rajaiah, D. J. Perkins, S. K. Polumuri, A. Zhao, A. D. Keegan, and S. N. Vogel
J. Immunol. 190, 4763-4772 (1 May 2013)

Sonic hedgehog-Dependent Induction of MicroRNA 31 and MicroRNA 150 Regulates Mycobacterium bovis BCG-Driven Toll-Like Receptor 2 Signaling
D. S. Ghorpade, S. Holla, S. V. Kaveri, J. Bayry, S. A. Patil, and K. N. Balaji
Mol. Cell. Biol. 33, 543-556 (1 February 2013)

Critical Roles of Glucocorticoid-Induced Leucine Zipper in Infectious Bursal Disease Virus (IBDV)-Induced Suppression of Type I Interferon Expression and Enhancement of IBDV Growth in Host Cells via Interaction with VP4
Z. Li, Y. Wang, X. Li, X. Li, H. Cao, and S. J. Zheng
J. Virol. 87, 1221-1231 (15 January 2013)

Deubiquitination of NF-{kappa}B by Ubiquitin-Specific Protease-7 promotes transcription
A. Colleran, P. E. Collins, C. O'Carroll, A. Ahmed, X. Mao, B. McManus, P. A. Kiely, E. Burstein, and R. J. Carmody
Proc. Natl. Acad. Sci. USA 110, 618-623 (8 January 2013)

Induction of Bcl-3 by acute binge alcohol results in Toll-like receptor 4/LPS tolerance
S. Bala, A. Tang, D. Catalano, J. Petrasek, O. Taha, K. Kodys, and G. Szabo
J. Leukoc. Biol. 92, 611-620 (1 September 2012)

Nuclear factor-{kappa}B binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome
Q. Yan, R. J. Carmody, Z. Qu, Q. Ruan, J. Jager, S. E. Mullican, M. A. Lazar, and Y. H. Chen
Proc. Natl. Acad. Sci. USA 109, 14140-14145 (28 August 2012)

NF-{kappa}B, the first quarter-century: remarkable progress and outstanding questions
M. S. Hayden, and S. Ghosh
Genes Dev. 26, 203-234 (1 February 2012)

IL-27 Enhances LPS-Induced Proinflammatory Cytokine Production via Upregulation of TLR4 Expression and Signaling in Human Monocytes
C. Guzzo, A. Ayer, S. Basta, B. W. Banfield, and K. Gee
J. Immunol. 188, 864-873 (15 January 2012)

The E3 ligase c-Cbl regulates dendritic cell activation
S.-H. Chiou, P. Shahi, R. T. Wagner, H. Hu, N. Lapteva, M. Seethammagari, S.-C. Sun, J. M. Levitt, and D. M. Spencer
EMBO Rep. 12, 971-979 (1 September 2011)

The I{kappa}B Family Member Bcl-3 Coordinates the Pulmonary Defense against Klebsiella pneumoniae Infection
F. Pene, A. Paun, S. U. Sonder, N. Rikhi, H. Wang, E. Claudio, and U. Siebenlist
J. Immunol. 186, 2412-2421 (15 February 2011)

Characterization of an Interferon-stimulated Response Element (ISRE) in the Il23a Promoter
S. Z. Sheikh, T. Kobayashi, K. Matsuoka, J. C. Onyiah, and S. E. Plevy
J Biol Chem 286, 1174-1180 (14 January 2011)

IFN-{gamma} abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling
J. Chen, and L. B. Ivashkiv
Proc. Natl. Acad. Sci. USA 107, 19438-19443 (9 November 2010)

Roles of Bcl-3 in the Pathogenesis of Murine Type 1 Diabetes
Q. Ruan, S.-J. Zheng, S. Palmer, R. J. Carmody, and Y. H. Chen
Diabetes 59, 2549-2557 (1 October 2010)

The Repressing Function of the Oncoprotein BCL-3 Requires CtBP, while Its Polyubiquitination and Degradation Involve the E3 Ligase TBLR1
A. Keutgens, K. Shostak, P. Close, X. Zhang, B. Hennuy, M. Aussems, J.-P. Chapelle, P. Viatour, A. Gothot, M. Fillet et al.
Mol. Cell. Biol. 30, 4006-4021 (15 August 2010)

I{kappa}B{eta}, a nuclear I{kappa}B protein, positively regulates the NF-{kappa}B-mediated expression of proinflammatory cytokines
S. Yamauchi, H. Ito, and A. Miyajima
Proc. Natl. Acad. Sci. USA 107, 11924-11929 (29 June 2010)

NF-{kappa}B Signaling: A Tale of Two Pathways in Skeletal Myogenesis
N. Bakkar, and D. C. Guttridge
Physiol. Rev. 90, 495-511 (1 April 2010)

Immediate mediators of the inflammatory response are poised for gene activation through RNA polymerase II stalling
K. Adelman, M. A. Kennedy, S. Nechaev, D. A. Gilchrist, G. W. Muse, Y. Chinenov, and I. Rogatsky
Proc. Natl. Acad. Sci. USA 106, 18207-18212 (27 October 2009)

Tumor Necrosis Factor-{alpha} Induces RelA Degradation via Ubiquitination at Lysine 195 to Prevent Excessive Nuclear Factor-{kappa}B Activation
Y. Fan, R. Mao, Y. Zhao, Y. Yu, W. Sun, P. Song, Z. Shi, D. Zhang, E. Yvon, H. Zhang et al.
J Biol Chem 284, 29290-29297 (23 October 2009)

Specification of DNA Binding Activity of NF-{kappa}B Proteins
F. Wan, and M. J. Lenardo
Cold Spring Harb. Perspect. Biol. 1, a000067-a000067 (1 October 2009)

The NF-{kappa}B Family of Transcription Factors and Its Regulation
A. Oeckinghaus, and S. Ghosh
Cold Spring Harb. Perspect. Biol. 1, a000034-a000034 (1 October 2009)

Validation-based insertional mutagenesis identifies lysine demethylase FBXL11 as a negative regulator of NF{kappa}B
T. Lu, M. W. Jackson, A. D. Singhi, E. S. Kandel, M. Yang, Y. Zhang, A. V. Gudkov, and G. R. Stark
Proc. Natl. Acad. Sci. USA 106, 16339-16344 (22 September 2009)

Impaired M. tuberculosis-mediated apoptosis in alveolar macrophages from HIV+ persons: potential role of IL-10 and BCL-3
N. R. Patel, K. Swan, X. Li, S. D. Tachado, and H. Koziel
J. Leukoc. Biol. 86, 53-60 (1 July 2009)

Phosphorylation of NF-{kappa}B p65 at Ser468 controls its COMMD1-dependent ubiquitination and target gene-specific proteasomal elimination
H. Geng, T. Wittwer, O. Dittrich-Breiholz, M. Kracht, and M. L. Schmitz
EMBO Rep. 10, 381-386 (1 April 2009)

Differential NF-{kappa}B pathways induction by Lactobacillus plantarum in the duodenum of healthy humans correlating with immune tolerance
P. van Baarlen, F. J. Troost, S. van Hemert, C. van der Meer, W. M. de Vos, P. J. de Groot, G. J. E. J. Hooiveld, R.-J. M. Brummer, and M. Kleerebezem
Proc. Natl. Acad. Sci. USA 106, 2371-2376 (17 February 2009)

Dendritic Cells and Monocyte/Macrophages That Create the IL-6/APRIL-Rich Lymph Node Microenvironments Where Plasmablasts Mature
E. Mohr, K. Serre, R. A. Manz, A. F. Cunningham, M. Khan, D. L. Hardie, R. Bird, and I. C. M. MacLennan
J. Immunol. 182, 2113-2123 (15 February 2009)

The Proto-Oncogene Bcl3, Induced by Tax, Represses Tax-Mediated Transcription via p300 Displacement from the Human T-Cell Leukemia Virus Type 1 Promoter
Y.-M. Kim, N. Sharma, and J. K. Nyborg
J. Virol. 82, 11939-11947 (1 December 2008)

Identification of lysine residues critical for the transcriptional activity and polyubiquitination of the NF-{kappa}B family member RelB
J. Leidner, L. Palkowitsch, U. Marienfeld, D. Fischer, and R. Marienfeld
Biochem. J. 416, 117-127 (15 November 2008)

Enhanced Resistance of Restraint-Stressed Mice to Sepsis
Y. Wang, Y. Lu, D. Yu, Y. Wang, F. Chen, H. Yang, and S. J. Zheng
J. Immunol. 181, 3441-3448 (1 September 2008)

Selection and characterization of anti-NF-{kappa}B p65 RNA aptamers
S. E. Wurster, and L. J. Maher
RNA 14, 1037-1047 (1 June 2008)

Epstein-Barr Virus Latent Membrane Protein 1 Induces Expression of the Epidermal Growth Factor Receptor through Effects on Bcl-3 and STAT3
C.-P. Kung, and N. Raab-Traub
J. Virol. 82, 5486-5493 (1 June 2008)

Impaired Bcl3 Up-regulation Leads to Enhanced Lipopolysaccharide-induced Interleukin (IL)-23P19 Gene Expression in IL-10-/- Mice
M. Muhlbauer, P. M. Chilton, T. C. Mitchell, and C. Jobin
J Biol Chem 283, 14182-14189 (23 May 2008)

A Novel CCCH-Zinc Finger Protein Family Regulates Proinflammatory Activation of Macrophages
J. Liang, J. Wang, A. Azfer, W. Song, G. Tromp, P. E. Kolattukudy, and M. Fu
J Biol Chem 283, 6337-6346 (7 March 2008)

Nuclear Ubiquitin Ligases, NF-{kappa}B Degradation, and the Control of Inflammation
G. Natoli, and S. Chiocca
Sci Signal 1, pe1-pe1 (8 January 2008)

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882