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.


Logo for

Science 318 (5856): 1628-1632

Copyright © 2007 by the American Association for the Advancement of Science

DUBA: A Deubiquitinase That Regulates Type I Interferon Production

Nobuhiko Kayagaki,1 Qui Phung,2 Salina Chan,1 Ruchir Chaudhari,1 Casey Quan,1 Karen M. O'Rourke,1 Michael Eby,1 Eric Pietras,3 Genhong Cheng,3 J. Fernando Bazan,4 Zemin Zhang,5 David Arnott,2 Vishva M. Dixit1*

Abstract: Production of type I interferon (IFN-I) is a critical host defense triggered by pattern-recognition receptors (PRRs) of the innate immune system. Deubiquitinating enzyme A (DUBA), an ovarian tumor domain-containing deubiquitinating enzyme, was discovered in a small interfering RNA–based screen as a regulator of IFN-I production. Reduction of DUBA augmented the PRR-induced IFN-I response, whereas ectopic expression of DUBA had the converse effect. DUBA bound tumor necrosis factor receptor–associated factor 3 (TRAF3), an adaptor protein essential for the IFN-I response. TRAF3 is an E3 ubiquitin ligase that preferentially assembled lysine-63–linked polyubiquitin chains. DUBA selectively cleaved the lysine-63–linked polyubiquitin chains on TRAF3, resulting in its dissociation from the downstream signaling complex containing TANK-binding kinase 1. A discrete ubiquitin interaction motif within DUBA was required for efficient deubiquitination of TRAF3 and optimal suppression of IFN-I. Our data identify DUBA as a negative regulator of innate immune responses.

1 Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA.
2 Department of Protein Chemistry, Genentech, South San Francisco, CA 94080, USA.
3 Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
4 Department of Protein Engineering, Genentech, South San Francisco, CA 94080, USA.
5 Department of Bioinformatics, Genentech, South San Francisco, CA 94080, USA.

* To whom correspondence should be addressed. E-mail: dixit{at}

Proteolytic processing, deubiquitinase and interferon antagonist activities of Middle East respiratory syndrome coronavirus papain-like protease.
X. Yang, X. Chen, G. Bian, J. Tu, Y. Xing, Y. Wang, and Z. Chen (2014)
J. Gen. Virol. 95, 614-626
   Abstract »    Full Text »    PDF »
USP21 negatively regulates antiviral response by acting as a RIG-I deubiquitinase.
Y. Fan, R. Mao, Y. Yu, S. Liu, Z. Shi, J. Cheng, H. Zhang, L. An, Y. Zhao, X. Xu, et al. (2014)
J. Exp. Med. 211, 313-328
   Abstract »    Full Text »    PDF »
Ubiquitin-interacting Motifs Confer Full Catalytic Activity, but Not Ubiquitin Chain Substrate Specificity, to Deubiquitinating Enzyme USP37.
H. Tanno, T. Shigematsu, S. Nishikawa, A. Hayakawa, K. Denda, T. Tanaka, and M. Komada (2014)
J. Biol. Chem. 289, 2415-2423
   Abstract »    Full Text »    PDF »
Ubiquitin in the immune system.
J. Zinngrebe, A. Montinaro, N. Peltzer, and H. Walczak (2014)
EMBO Rep. 15, 28-45
   Abstract »    Full Text »    PDF »
The Ubiquitin-Specific Protease USP15 Promotes RIG-I-Mediated Antiviral Signaling by Deubiquitylating TRIM25.
E.-K. Pauli, Y. K. Chan, M. E. Davis, S. Gableske, M. K. Wang, K. F. Feister, and M. U. Gack (2014)
Science Signaling 7, ra3
   Abstract »    Full Text »    PDF »
Herpes Simplex Virus 1 Ubiquitin-Specific Protease UL36 Inhibits Beta Interferon Production by Deubiquitinating TRAF3.
S. Wang, K. Wang, J. Li, and C. Zheng (2013)
J. Virol. 87, 11851-11860
   Abstract »    Full Text »    PDF »
Depletion of the 26S Proteasome Adaptor Ecm29 Increases Toll-Like Receptor 3 Signaling.
C. Gorbea, M. Rechsteiner, J. G. Vallejo, and N. E. Bowles (2013)
Science Signaling 6, ra86
   Abstract »    Full Text »    PDF »
Deubiquitylases From Genes to Organism.
M. J. Clague, I. Barsukov, J. M. Coulson, H. Liu, D. J. Rigden, and S. Urbe (2013)
Physiol Rev 93, 1289-1315
   Abstract »    Full Text »    PDF »
The papain-like protease of porcine epidemic diarrhea virus negatively regulates type I interferon pathway by acting as a viral deubiquitinase.
Y. Xing, J. Chen, J. Tu, B. Zhang, X. Chen, H. Shi, S. C. Baker, L. Feng, and Z. Chen (2013)
J. Gen. Virol. 94, 1554-1567
   Abstract »    Full Text »    PDF »
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 »
Epstein-Barr Virus Deubiquitinase Downregulates TRAF6-Mediated NF-{kappa}B Signaling during Productive Replication.
S. Saito, T. Murata, T. Kanda, H. Isomura, Y. Narita, A. Sugimoto, D. Kawashima, and T. Tsurumi (2013)
J. Virol. 87, 4060-4070
   Abstract »    Full Text »    PDF »
Deubiquitinase function of arterivirus papain-like protease 2 suppresses the innate immune response in infected host cells.
P. B. van Kasteren, B. A. Bailey-Elkin, T. W. James, D. K. Ninaber, C. Beugeling, M. Khajehpour, E. J. Snijder, B. L. Mark, and M. Kikkert (2013)
PNAS 110, E838-E847
   Abstract »    Full Text »    PDF »
The Ankrd 13 family of UIM-bearing proteins regulates EGF receptor endocytosis from the plasma membrane.
H. Tanno, T. Yamaguchi, E. Goto, S. Ishido, and M. Komada (2012)
Mol. Biol. Cell 23, 1343-1353
   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 »
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 »
MIP-T3 Is a Negative Regulator of Innate Type I IFN Response.
M.-H. J. Ng, T.-H. Ho, K.-H. Kok, K.-L. Siu, J. Li, and D.-Y. Jin (2011)
J. Immunol. 187, 6473-6482
   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 »
SENP2 negatively regulates cellular antiviral response by deSUMOylating IRF3 and conditioning it for ubiquitination and degradation.
Y. Ran, T.-T. Liu, Q. Zhou, S. Li, A.-P. Mao, Y. Li, L.-J. Liu, J.-K. Cheng, and H.-B. Shu (2011)
J Mol Cell Biol 3, 283-292
   Abstract »    Full Text »    PDF »
Functional analysis of the RNF114 psoriasis susceptibility gene implicates innate immune responses to double-stranded RNA in disease pathogenesis.
M.-J. Bijlmakers, S. K. Kanneganti, J. N. Barker, R. C. Trembath, and F. Capon (2011)
Hum. Mol. Genet. 20, 3129-3137
   Abstract »    Full Text »    PDF »
The Leader Proteinase of Foot-and-Mouth Disease Virus Negatively Regulates the Type I Interferon Pathway by Acting as a Viral Deubiquitinase.
D. Wang, L. Fang, P. Li, L. Sun, J. Fan, Q. Zhang, R. Luo, X. Liu, K. Li, H. Chen, et al. (2011)
J. Virol. 85, 3758-3766
   Abstract »    Full Text »    PDF »
Structural Analysis of a Viral Ovarian Tumor Domain Protease from the Crimean-Congo Hemorrhagic Fever Virus in Complex with Covalently Bonded Ubiquitin.
G. C. Capodagli, M. A. McKercher, E. A. Baker, E. M. Masters, J. S. Brunzelle, and S. D. Pegan (2011)
J. Virol. 85, 3621-3630
   Abstract »    Full Text »    PDF »
ARF-like Protein 16 (ARL16) Inhibits RIG-I by Binding with Its C-terminal Domain in a GTP-dependent Manner.
Y.-K. Yang, H. Qu, D. Gao, W. Di, H.-W. Chen, X. Guo, Z.-H. Zhai, and D.-Y. Chen (2011)
J. Biol. Chem. 286, 10568-10580
   Abstract »    Full Text »    PDF »
Structural basis for the removal of ubiquitin and interferon-stimulated gene 15 by a viral ovarian tumor domain-containing protease.
T. W. James, N. Frias-Staheli, J.-P. Bacik, J. M. Levingston Macleod, M. Khajehpour, A. Garcia-Sastre, and B. L. Mark (2011)
PNAS 108, 2222-2227
   Abstract »    Full Text »    PDF »
Molecular basis for ubiquitin and ISG15 cross-reactivity in viral ovarian tumor domains.
M. Akutsu, Y. Ye, S. Virdee, J. W. Chin, and D. Komander (2011)
PNAS 108, 2228-2233
   Abstract »    Full Text »    PDF »
TNF Receptor-Associated Factor 3 Is Required for T Cell-Mediated Immunity and TCR/CD28 Signaling.
P. Xie, Z. J. Kraus, L. L. Stunz, Y. Liu, and G. A. Bishop (2011)
J. Immunol. 186, 143-155
   Abstract »    Full Text »    PDF »
Interleukin 1 receptor signaling regulates DUBA expression and facilitates Toll-like receptor 9-driven antiinflammatory cytokine production.
J. M. Gonzalez-Navajas, J. Law, K. P. Nguyen, M. Bhargava, M. P. Corr, N. Varki, L. Eckmann, H. M. Hoffman, J. Lee, and E. Raz (2010)
J. Exp. Med. 207, 2799-2807
   Abstract »    Full Text »    PDF »
MCP-induced protein 1 deubiquitinates TRAF proteins and negatively regulates JNK and NF-{kappa}B signaling.
J. Liang, Y. Saad, T. Lei, J. Wang, D. Qi, Q. Yang, P. E. Kolattukudy, and M. Fu (2010)
J. Exp. Med. 207, 2959-2973
   Abstract »    Full Text »    PDF »
Deubiquitinase Inhibition by Small-Molecule WP1130 Triggers Aggresome Formation and Tumor Cell Apoptosis.
V. Kapuria, L. F. Peterson, D. Fang, W. G. Bornmann, M. Talpaz, and N. J. Donato (2010)
Cancer Res. 70, 9265-9276
   Abstract »    Full Text »    PDF »
Polyubiquitin conjugation to NEMO by triparite motif protein 23 (TRIM23) is critical in antiviral defense.
K.-i. Arimoto, K. Funami, Y. Saeki, K. Tanaka, K. Okawa, O. Takeuchi, S. Akira, Y. Murakami, and K. Shimotohno (2010)
PNAS 107, 15856-15861
   Abstract »    Full Text »    PDF »
Identification of a Novel in Vivo Virus-targeted Phosphorylation Site in Interferon Regulatory Factor-3 (IRF3).
B. Bergstroem, I. B. Johnsen, T. T. Nguyen, L. Hagen, G. Slupphaug, L. Thommesen, and M. W. Anthonsen (2010)
J. Biol. Chem. 285, 24904-24914
   Abstract »    Full Text »    PDF »
The A20 Deubiquitinase Activity Negatively Regulates LMP1 Activation of IRF7.
S. Ning and J. S. Pagano (2010)
J. Virol. 84, 6130-6138
   Abstract »    Full Text »    PDF »
Positive Regulation of Interferon Regulatory Factor 3 Activation by Herc5 via ISG15 Modification.
H. X. Shi, K. Yang, X. Liu, X. Y. Liu, B. Wei, Y. F. Shan, L. H. Zhu, and C. Wang (2010)
Mol. Cell. Biol. 30, 2424-2436
   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 »
Deubiquitinating and Interferon Antagonism Activities of Coronavirus Papain-Like Proteases.
M. A. Clementz, Z. Chen, B. S. Banach, Y. Wang, L. Sun, K. Ratia, Y. M. Baez-Santos, J. Wang, J. Takayama, A. K. Ghosh, et al. (2010)
J. Virol. 84, 4619-4629
   Abstract »    Full Text »    PDF »
Regulation of Virus-triggered Signaling by OTUB1- and OTUB2-mediated Deubiquitination of TRAF3 and TRAF6.
S. Li, H. Zheng, A.-P. Mao, B. Zhong, Y. Li, Y. Liu, Y. Gao, Y. Ran, P. Tien, and H.-B. Shu (2010)
J. Biol. Chem. 285, 4291-4297
   Abstract »    Full Text »    PDF »
Lysine 63 Polyubiquitination in Immunotherapy and in Cancer-promoting Inflammation.
I. Martinez-Forero, A. Rouzaut, A. Palazon, J. Dubrot, and I. Melero (2009)
Clin. Cancer Res. 15, 6751-6757
   Abstract »    Full Text »    PDF »
Structural basis for specific recognition of Lys 63-linked polyubiquitin chains by tandem UIMs of RAP80.
Y. Sato, A. Yoshikawa, H. Mimura, M. Yamashita, A. Yamagata, and S. Fukai (2009)
EMBO J. 28, 2461-2468
   Abstract »    Full Text »    PDF »
Polo-like Kinase 1 (PLK1) Regulates Interferon (IFN) Induction by MAVS.
D. Vitour, S. Dabo, M. Ahmadi Pour, M. Vilasco, P.-O. Vidalain, Y. Jacob, M. Mezel-Lemoine, S. Paz, M. Arguello, R. Lin, et al. (2009)
J. Biol. Chem. 284, 21797-21809
   Abstract »    Full Text »    PDF »
MicroRNA-146a Feedback Inhibits RIG-I-Dependent Type I IFN Production in Macrophages by Targeting TRAF6, IRAK1, and IRAK2.
J. Hou, P. Wang, L. Lin, X. Liu, F. Ma, H. An, Z. Wang, and X. Cao (2009)
J. Immunol. 183, 2150-2158
   Abstract »    Full Text »    PDF »
The Tyrosine Kinase c-Src Enhances RIG-I (Retinoic Acid-inducible Gene I)-elicited Antiviral Signaling.
I. B. Johnsen, T. T. Nguyen, B. Bergstroem, K. A. Fitzgerald, and M. W. Anthonsen (2009)
J. Biol. Chem. 284, 19122-19131
   Abstract »    Full Text »    PDF »
Ubiquitin-Regulated Recruitment of I{kappa}B Kinase {varepsilon} to the MAVS Interferon Signaling Adapter.
S. Paz, M. Vilasco, M. Arguello, Q. Sun, J. Lacoste, T. L.-A. Nguyen, T. Zhao, E. A. Shestakova, S. Zaari, A. Bibeau-Poirier, et al. (2009)
Mol. Cell. Biol. 29, 3401-3412
   Abstract »    Full Text »    PDF »
Lymphocyte-specific TRAF3 transgenic mice have enhanced humoral responses and develop plasmacytosis, autoimmunity, inflammation, and cancer.
J. M. Zapata, D. Llobet, M. Krajewska, S. Lefebvre, C. L. Kress, and J. C. Reed (2009)
Blood 113, 4595-4603
   Abstract »    Full Text »    PDF »
MAVS Self-Association Mediates Antiviral Innate Immune Signaling.
E. D. Tang and C.-Y. Wang (2009)
J. Virol. 83, 3420-3428
   Abstract »    Full Text »    PDF »
The roles of TLRs, RLRs and NLRs in pathogen recognition.
T. Kawai and S. Akira (2009)
Int. Immunol. 21, 317-337
   Abstract »    Full Text »    PDF »
A20: Central Gatekeeper in Inflammation and Immunity.
B. Coornaert, I. Carpentier, and R. Beyaert (2009)
J. Biol. Chem. 284, 8217-8221
   Abstract »    Full Text »    PDF »
Role of Non-degradative Ubiquitination in Interleukin-1 and Toll-like Receptor Signaling.
S. E. Keating and A. G. Bowie (2009)
J. Biol. Chem. 284, 8211-8215
   Full Text »    PDF »
UAF1 Is a Subunit of Multiple Deubiquitinating Enzyme Complexes.
M. A. Cohn, Y. Kee, W. Haas, S. P. Gygi, and A. D. D'Andrea (2009)
J. Biol. Chem. 284, 5343-5351
   Abstract »    Full Text »    PDF »
TLRs and innate immunity.
B. A. Beutler (2009)
Blood 113, 1399-1407
   Abstract »    Full Text »    PDF »
Attenuated Expression of A20 Markedly Increases the Efficacy of Double-Stranded RNA-Activated Dendritic Cells As an Anti-Cancer Vaccine.
K. Breckpot, C. Aerts-Toegaert, C. Heirman, U. Peeters, R. Beyaert, J. L. Aerts, and K. Thielemans (2009)
J. Immunol. 182, 860-870
   Abstract »    Full Text »    PDF »
Riplet/RNF135, a RING Finger Protein, Ubiquitinates RIG-I to Promote Interferon-{beta} Induction during the Early Phase of Viral Infection.
H. Oshiumi, M. Matsumoto, S. Hatakeyama, and T. Seya (2009)
J. Biol. Chem. 284, 807-817
   Abstract »    Full Text »    PDF »
FLN29 Deficiency Reveals Its Negative Regulatory Role in the Toll-like Receptor (TLR) and Retinoic Acid-inducible Gene I (RIG-I)-like Helicase Signaling Pathway.
T. Sanada, G. Takaesu, R. Mashima, R. Yoshida, T. Kobayashi, and A. Yoshimura (2008)
J. Biol. Chem. 283, 33858-33864
   Abstract »    Full Text »    PDF »
Proteases: Multifunctional Enzymes in Life and Disease.
C. Lopez-Otin and J. S. Bond (2008)
J. Biol. Chem. 283, 30433-30437
   Full Text »    PDF »
TRAF6 and the Three C-Terminal Lysine Sites on IRF7 Are Required for Its Ubiquitination-Mediated Activation by the Tumor Necrosis Factor Receptor Family Member Latent Membrane Protein 1.
S. Ning, A. D. Campos, B. G. Darnay, G. L. Bentz, and J. S. Pagano (2008)
Mol. Cell. Biol. 28, 6536-6546
   Abstract »    Full Text »    PDF »
The Deubiquitinating Enzyme Ataxin-3, a Polyglutamine Disease Protein, Edits Lys63 Linkages in Mixed Linkage Ubiquitin Chains.
B. J. Winborn, S. M. Travis, S. V. Todi, K. M. Scaglione, P. Xu, A. J. Williams, R. E. Cohen, J. Peng, and H. L. Paulson (2008)
J. Biol. Chem. 283, 26436-26443
   Abstract »    Full Text »    PDF »
The NY-1 Hantavirus Gn Cytoplasmic Tail Coprecipitates TRAF3 and Inhibits Cellular Interferon Responses by Disrupting TBK1-TRAF3 Complex Formation.
P. J. Alff, N. Sen, E. Gorbunova, I. N. Gavrilovskaya, and E. R. Mackow (2008)
J. Virol. 82, 9115-9122
   Abstract »    Full Text »    PDF »
Regulation of I{kappa}B Kinase-related Kinases and Antiviral Responses by Tumor Suppressor CYLD.
M. Zhang, X. Wu, A. J. Lee, W. Jin, M. Chang, A. Wright, T. Imaizumi, and S.-C. Sun (2008)
J. Biol. Chem. 283, 18621-18626
   Abstract »    Full Text »    PDF »
Homo-oligomerization Is Essential for Toll/Interleukin-1 Receptor Domain-containing Adaptor Molecule-1-mediated NF-{kappa}B and Interferon Regulatory Factor-3 Activation.
K. Funami, M. Sasai, H. Oshiumi, T. Seya, and M. Matsumoto (2008)
J. Biol. Chem. 283, 18283-18291
   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