Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 327 (5969): 1135-1139

Copyright © 2010 by the American Association for the Advancement of Science

Inhibition of NF-{kappa}B Signaling by A20 Through Disruption of Ubiquitin Enzyme Complexes

Noula Shembade,1,* Averil Ma,2 Edward W. Harhaj1,*

Abstract: A20 negatively regulates inflammation by inhibiting the nuclear factor {kappa}B (NF-{kappa}B) transcription factor in the tumor necrosis factor–receptor (TNFR) and Toll-like receptor (TLR) pathways. A20 contains deubiquitinase and E3 ligase domains and thus has been proposed to function as a ubiquitin-editing enzyme downstream of TNFR1 by inactivating ubiquitinated RIP1. However, it remains unclear how A20 terminates NF-{kappa}B signaling downstream of TLRs. We have shown that A20 inhibited the E3 ligase activities of TRAF6, TRAF2, and cIAP1 by antagonizing interactions with the E2 ubiquitin conjugating enzymes Ubc13 and UbcH5c. A20, together with the regulatory molecule TAX1BP1, interacted with Ubc13 and UbcH5c and triggered their ubiquitination and proteasome-dependent degradation. These findings suggest mechanism of A20 action in the inhibition of inflammatory signaling pathways.

1 Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, The University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
2 Department of Medicine, University of California at San Francisco, San Francisco, CA 94143, USA.

* To whom correspondence should be addressed. E-mail: nshembade{at}med.miami.edu (N.S.); eharhaj{at}med.miami.edu (E.W.H.)

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Ubiquitin-Specific Protease 25 Regulates TLR4-Dependent Innate Immune Responses Through Deubiquitination of the Adaptor Protein TRAF3.
B. Zhong, X. Liu, X. Wang, X. Liu, H. Li, B. G. Darnay, X. Lin, S.-C. Sun, and C. Dong (2013)
Science Signaling 6, ra35
   Abstract »    Full Text »    PDF »
Recognition of pathogen-associated nucleic acids by endosomal nucleic acid-sensing toll-like receptors.
X. He, H. Jia, Z. Jing, and D. Liu (2013)
Acta Biochim Biophys Sin 45, 241-258
   Abstract »    Full Text »    PDF »
USP2a negatively regulates IL-1{beta}- and virus-induced NF-{kappa}B activation by deubiquitinating TRAF6.
X. He, Y. Li, C. Li, L.-J. Liu, X.-D. Zhang, Y. Liu, and H.-B. Shu (2013)
J Mol Cell Biol 5, 39-47
   Abstract »    Full Text »    PDF »
Lysine 63-linked Ubiquitination Modulates Mixed Lineage Kinase-3 Interaction with JIP1 Scaffold Protein in Cytokine-induced Pancreatic {beta} Cell Death.
R. K. Humphrey, S. M. A. Yu, A. Bellary, S. Gonuguntla, M. Yebra, and U. S. Jhala (2013)
J. Biol. Chem. 288, 2428-2440
   Abstract »    Full Text »    PDF »
A20 and CYLD Do Not Share Significant Overlapping Functions during B Cell Development and Activation.
Y. Chu, V. Soberon, L. Glockner, R. Beyaert, R. Massoumi, G. van Loo, D. Krappmann, and M. Schmidt-Supprian (2012)
J. Immunol. 189, 4437-4443
   Abstract »    Full Text »    PDF »
{beta}-TrCP-Mediated IRAK1 Degradation Releases TAK1-TRAF6 from the Membrane to the Cytosol for TAK1-Dependent NF-{kappa}B Activation.
W. Cui, N. Xiao, H. Xiao, H. Zhou, M. Yu, J. Gu, and X. Li (2012)
Mol. Cell. Biol. 32, 3990-4000
   Abstract »    Full Text »    PDF »
Leishmania donovani Exploits Host Deubiquitinating Enzyme A20, a Negative Regulator of TLR Signaling, To Subvert Host Immune Response.
S. Srivastav, S. Kar, A. G. Chande, R. Mukhopadhyaya, and P. K. Das (2012)
J. Immunol. 189, 924-934
   Abstract »    Full Text »    PDF »
MicroRNAs miR-125a and miR-125b constitutively activate the NF-{kappa}B pathway by targeting the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20).
S.-W. Kim, K. Ramasamy, H. Bouamar, A.-P. Lin, D. Jiang, and R. C. T. Aguiar (2012)
PNAS 109, 7865-7870
   Abstract »    Full Text »    PDF »
Ubiquitin-specific Protease 4 Mitigates Toll-like/Interleukin-1 Receptor Signaling and Regulates Innate Immune Activation.
F. Zhou, X. Zhang, H. van Dam, P. ten Dijke, H. Huang, and L. Zhang (2012)
J. Biol. Chem. 287, 11002-11010
   Abstract »    Full Text »    PDF »
An RNA Interference Screen Identifies the Deubiquitinase STAMBPL1 as a Critical Regulator of Human T-Cell Leukemia Virus Type 1 Tax Nuclear Export and NF-{kappa}B Activation.
A. Lavorgna and E. W. Harhaj (2012)
J. Virol. 86, 3357-3369
   Abstract »    Full Text »    PDF »
Emerging Role of Ubiquitination in Antiviral RIG-I Signaling.
J. Maelfait and R. Beyaert (2012)
Microbiol. Mol. Biol. Rev. 76, 33-45
   Abstract »    Full Text »    PDF »
Signaling in Innate Immunity and Inflammation.
K. Newton and V. M. Dixit (2012)
Cold Spring Harb Perspect Biol 4, a006049
   Abstract »    Full Text »    PDF »
A20 Ubiquitin Ligase-Mediated Polyubiquitination of RIP1 Inhibits Caspase-8 Cleavage and TRAIL-Induced Apoptosis in Glioblastoma.
A. C. Bellail, J. J. Olson, X. Yang, Z. J. Chen, and C. Hao (2012)
Cancer Discovery 2, 140-155
   Abstract »    Full Text »    PDF »
Arterivirus and Nairovirus Ovarian Tumor Domain-Containing Deubiquitinases Target Activated RIG-I To Control Innate Immune Signaling.
P. B. van Kasteren, C. Beugeling, D. K. Ninaber, N. Frias-Staheli, S. van Boheemen, A. Garcia-Sastre, E. J. Snijder, and M. Kikkert (2012)
J. Virol. 86, 773-785
   Abstract »    Full Text »    PDF »
Site-specific ubiquitination is required for relieving the transcription factor Miz1-mediated suppression on TNF-{alpha}-induced JNK activation and inflammation.
J. Liu, J. Yan, S. Jiang, J. Wen, L. Chen, Y. Zhao, and A. Lin (2012)
PNAS 109, 191-196
   Abstract »    Full Text »    PDF »
Neurodegenerative and Inflammatory Pathway Components Linked to TNF-{alpha}/TNFR1 Signaling in the Glaucomatous Human Retina.
X. Yang, C. Luo, J. Cai, D. W. Powell, D. Yu, M. H. Kuehn, and G. Tezel (2011)
Invest. Ophthalmol. Vis. Sci. 52, 8442-8454
   Abstract »    Full Text »    PDF »
ABIN1 Protein Cooperates with TAX1BP1 and A20 Proteins to Inhibit Antiviral Signaling.
L. Gao, H. Coope, S. Grant, A. Ma, S. C. Ley, and E. W. Harhaj (2011)
J. Biol. Chem. 286, 36592-36602
   Abstract »    Full Text »    PDF »
Ubiquitin-Specific Peptidase 20 Targets TRAF6 and Human T Cell Leukemia Virus Type 1 Tax To Negatively Regulate NF-{kappa}B Signaling.
J. Yasunaga, F. C. Lin, X. Lu, and K.-T. Jeang (2011)
J. Virol. 85, 6212-6219
   Abstract »    Full Text »    PDF »
IMPDHII Protein Inhibits Toll-like Receptor 2-mediated Activation of NF-{kappa}B.
J. Toubiana, A.-L. Rossi, D. Grimaldi, N. Belaidouni, P. Chafey, G. Clary, E. Courtine, F. Pene, J.-P. Mira, Y.-E. Claessens, et al. (2011)
J. Biol. Chem. 286, 23319-23333
   Abstract »    Full Text »    PDF »
A20 Is Induced by Kaposi Sarcoma-associated Herpesvirus-encoded Viral FLICE Inhibitory Protein (vFLIP) K13 and Blocks K13-induced Nuclear Factor-{kappa}B in a Negative Feedback Manner.
H. Matta, R. Gopalakrishnan, V. Punj, H. Yi, Y. Suo, and P. M. Chaudhary (2011)
J. Biol. Chem. 286, 21555-21564
   Abstract »    Full Text »    PDF »
A20 Regulation of Nuclear Factor-{kappa}B: Perspectives for Inflammatory Lung Disease.
C. Kelly, M. D. Shields, J. S. Elborn, and B. C. Schock (2011)
44, 743-748
   Abstract »    Full Text »    PDF »
Endotoxin Tolerance Impairs IL-1 Receptor-Associated Kinase (IRAK) 4 and TGF-{beta}-activated Kinase 1 Activation, K63-linked Polyubiquitination and Assembly of IRAK1, TNF Receptor-associated Factor 6, and I{kappa}B Kinase {gamma} and Increases A20 Expression.
Y. Xiong, F. Qiu, W. Piao, C. Song, L. M. Wahl, and A. E. Medvedev (2011)
J. Biol. Chem. 286, 7905-7916
   Abstract »    Full Text »    PDF »
B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice.
Y. Chu, J. C. Vahl, D. Kumar, K. Heger, A. Bertossi, E. Wojtowicz, V. Soberon, D. Schenten, B. Mack, M. Reutelshofer, et al. (2011)
Blood 117, 2227-2236
   Abstract »    Full Text »    PDF »
SLUG-induced Elevation of D1 Cyclin in Breast Cancer Cells through the Inhibition of Its Ubiquitination.
M. K. Mittal, K. Singh, S. Misra, and G. Chaudhuri (2011)
J. Biol. Chem. 286, 469-479
   Abstract »    Full Text »    PDF »
Tumor Necrosis Factor {alpha}-induced Inflammation Is Increased but Apoptosis Is Inhibited by Common Food Additive Carrageenan.
S. Bhattacharyya, P. K. Dudeja, and J. K. Tobacman (2010)
J. Biol. Chem. 285, 39511-39522
   Abstract »    Full Text »    PDF »
TAX1BP1 and A20 Inhibit Antiviral Signaling by Targeting TBK1-IKKi Kinases.
K. Parvatiyar, G. N. Barber, and E. W. Harhaj (2010)
J. Biol. Chem. 285, 14999-15009
   Abstract »    Full Text »    PDF »
Turning Off Inflammation Signaling.
S. Sriskantharajah and S. C. Ley (2010)
Science 327, 1093-1094
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

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