Error message

No crossref credentials set for sci

A Deubiquitinase That Regulates Type I Interferon Production

Science, 7 December 2007
Vol. 318, Issue 5856, p. 1628-1632
DOI: 10.1126/science.1145918

A Deubiquitinase That Regulates Type I Interferon Production

  1. Nobuhiko Kayagaki1,
  2. Qui Phung2,
  3. Salina Chan1,
  4. Ruchir Chaudhari1,
  5. Casey Quan1,
  6. Karen M. O'Rourke1,
  7. Michael Eby1,
  8. Eric Pietras3,
  9. Genhong Cheng3,
  10. J. Fernando Bazan4,
  11. Zemin Zhang5,
  12. David Arnott2,
  13. Vishva M. Dixit1,*
  1. 1 Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA.
  2. 2 Department of Protein Chemistry, Genentech, South San Francisco, CA 94080, USA.
  3. 3 Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
  4. 4 Department of Protein Engineering, Genentech, South San Francisco, CA 94080, USA.
  5. 5 Department of Bioinformatics, Genentech, South San Francisco, CA 94080, USA.
  1. * To whom correspondence should be addressed. E-mail: dixit{at}


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.

  • Received for publication 31 May 2007.
  • Accepted for publication 30 October 2007.


N. Kayagaki, Q. Phung, S. Chan, R. Chaudhari, C. Quan, K. M. O'Rourke, M. Eby, E. Pietras, G. Cheng, J. F. Bazan, Z. Zhang, D. Arnott, and V. M. Dixit, A Deubiquitinase That Regulates Type I Interferon Production. Science 318, 1628-1632 (2007).

Regulation of cellular innate antiviral signaling by ubiquitin modification
D. Lin, and B. Zhong
Acta Biochim Biophys Sin 47, 149-155 (1 March 2015)

DUBs, the regulation of cell identity and disease
J. Heideker, and I. E. Wertz
Biochem. J. 465, 1-26 (1 January 2015)

Ubiquitin-Specific Protease 2b Negatively Regulates IFN-{beta} Production and Antiviral Activity by Targeting TANK-Binding Kinase 1
L. Zhang, X. Zhao, M. Zhang, W. Zhao, and C. Gao
J. Immunol. 193, 2230-2237 (1 September 2014)

Novel Roles of Cytoplasmic ICP0: Proteasome-Independent Functions of the RING Finger Are Required To Block Interferon-Stimulated Gene Production but Not To Promote Viral Replication
K. E. Taylor, M. V. Chew, A. A. Ashkar, and K. L. Mossman
J. Virol. 88, 8091-8101 (15 July 2014)

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
J. Gen. Virol. 95, 614-626 (1 March 2014)

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.
JEM 211, 313-328 (10 February 2014)

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
J Biol Chem 289, 2415-2423 (24 January 2014)

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
Sci Signal 7, ra3-ra3 (7 January 2014)

Ubiquitin in the immune system
J. Zinngrebe, A. Montinaro, N. Peltzer, and H. Walczak
EMBO Rep. 15, 28-45 (1 January 2014)

Herpes Simplex Virus 1 Ubiquitin-Specific Protease UL36 Inhibits Beta Interferon Production by Deubiquitinating TRAF3
S. Wang, K. Wang, J. Li, and C. Zheng
J. Virol. 87, 11851-11860 (1 November 2013)

Depletion of the 26S Proteasome Adaptor Ecm29 Increases Toll-Like Receptor 3 Signaling
C. Gorbea, M. Rechsteiner, J. G. Vallejo, and N. E. Bowles
Sci Signal 6, ra86-ra86 (1 October 2013)

Deubiquitylases From Genes to Organism
M. J. Clague, I. Barsukov, J. M. Coulson, H. Liu, D. J. Rigden, and S. Urbe
Physiol. Rev. 93, 1289-1315 (1 July 2013)

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
J. Gen. Virol. 94, 1554-1567 (1 July 2013)

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
Sci Signal 6, ra35-ra35 (14 May 2013)

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
J. Virol. 87, 4060-4070 (1 April 2013)

Recognition of pathogen-associated nucleic acids by endosomal nucleic acid-sensing toll-like receptors
X. He, H. Jia, Z. Jing, and D. Liu
Acta Biochim Biophys Sin 45, 241-258 (1 April 2013)

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
Proc. Natl. Acad. Sci. USA 110, E838-E847 (26 February 2013)

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
Mol. Biol. Cell 23, 1343-1353 (1 April 2012)

Emerging Role of Ubiquitination in Antiviral RIG-I Signaling
J. Maelfait, and R. Beyaert
Microbiol. Mol. Biol. Rev. 76, 33-45 (1 March 2012)

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
J. Virol. 86, 773-785 (15 January 2012)

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
J. Immunol. 187, 6473-6482 (15 December 2011)

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
J Biol Chem 286, 36592-36602 (21 October 2011)

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
J Mol Cell Biol 3, 283-292 (1 October 2011)

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
Hum Mol Genet 20, 3129-3137 (15 August 2011)

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.
J. Virol. 85, 3758-3766 (15 April 2011)

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
J. Virol. 85, 3621-3630 (1 April 2011)

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
J Biol Chem 286, 10568-10580 (25 March 2011)

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
Proc. Natl. Acad. Sci. USA 108, 2228-2233 (8 February 2011)

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
Proc. Natl. Acad. Sci. USA 108, 2222-2227 (8 February 2011)

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
J. Immunol. 186, 143-155 (1 January 2011)

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
JEM 207, 2959-2973 (20 December 2010)

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, E. Raz et al.
JEM 207, 2799-2807 (20 December 2010)

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
Cancer Res. 70, 9265-9276 (15 November 2010)

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
Proc. Natl. Acad. Sci. USA 107, 15856-15861 (7 September 2010)

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
J Biol Chem 285, 24904-24914 (6 August 2010)

The A20 Deubiquitinase Activity Negatively Regulates LMP1 Activation of IRF7
S. Ning, and J. S. Pagano
J. Virol. 84, 6130-6138 (15 June 2010)

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
Mol. Cell. Biol. 30, 2424-2436 (15 May 2010)

TAX1BP1 and A20 Inhibit Antiviral Signaling by Targeting TBK1-IKKi Kinases
K. Parvatiyar, G. N. Barber, and E. W. Harhaj
J Biol Chem 285, 14999-15009 (14 May 2010)

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.
J. Virol. 84, 4619-4629 (1 May 2010)

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, H.-B. Shu et al.
J Biol Chem 285, 4291-4297 (12 February 2010)

A new map to understand deubiquitination
E. J. Katz, M. Isasa, and B. Crosas
Biochm. Soc. Trans. 38, 21-28 (1 February 2010)

Lysine 63 Polyubiquitination in Immunotherapy and in Cancer-promoting Inflammation
I. Martinez-Forero, A. Rouzaut, A. Palazon, J. Dubrot, and I. Melero
Clin. Cancer Res. 15, 6751-6757 (15 November 2009)

The emerging complexity of protein ubiquitination
D. Komander, A. Rouzaut, A. Palazon, J. Dubrot, and I. Melero
Biochm. Soc. Trans. 37, 937-953 (1 October 2009)

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
EMBO J. 28, 2461-2468 (19 August 2009)

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.
J Biol Chem 284, 21797-21809 (14 August 2009)

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
J. Immunol. 183, 2150-2158 (1 August 2009)

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
J Biol Chem 284, 19122-19131 (10 July 2009)

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.
Mol. Cell. Biol. 29, 3401-3412 (15 June 2009)

Pathogen recognition in the innate immune response
H. Kumar, T. Kawai, and S. Akira
Biochem. J. 420, 1-16 (15 May 2009)

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
Blood 113, 4595-4603 (7 May 2009)

MAVS Self-Association Mediates Antiviral Innate Immune Signaling
E. D. Tang, and C.-Y. Wang
J. Virol. 83, 3420-3428 (15 April 2009)

The roles of TLRs, RLRs and NLRs in pathogen recognition
T. Kawai, and S. Akira
Int Immunol 21, 317-337 (1 April 2009)

Role of Non-degradative Ubiquitination in Interleukin-1 and Toll-like Receptor Signaling
S. E. Keating, and A. G. Bowie
J Biol Chem 284, 8211-8215 (27 March 2009)

A20: Central Gatekeeper in Inflammation and Immunity
B. Coornaert, I. Carpentier, and R. Beyaert
J Biol Chem 284, 8217-8221 (27 March 2009)

UAF1 Is a Subunit of Multiple Deubiquitinating Enzyme Complexes
M. A. Cohn, Y. Kee, W. Haas, S. P. Gygi, and A. D. D''Andrea
J Biol Chem 284, 5343-5351 (20 February 2009)

TLRs and innate immunity
B. A. Beutler, Y. Kee, W. Haas, S. P. Gygi, and A. D. D''Andrea
Blood 113, 1399-1407 (12 February 2009)

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
J. Immunol. 182, 860-870 (15 January 2009)

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
J Biol Chem 284, 807-817 (9 January 2009)

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
J Biol Chem 283, 33858-33864 (5 December 2008)

Proteases: Multifunctional Enzymes in Life and Disease
C. Lopez-Otin, and J. S. Bond
J Biol Chem 283, 30433-30437 (7 November 2008)

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
Mol. Cell. Biol. 28, 6536-6546 (15 October 2008)

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
J Biol Chem 283, 26436-26443 (26 September 2008)

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
J. Virol. 82, 9115-9122 (15 September 2008)

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
J Biol Chem 283, 18621-18626 (4 July 2008)

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
J Biol Chem 283, 18283-18291 (27 June 2008)

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