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 331 (6015): 330-334

Copyright © 2011 by the American Association for the Advancement of Science

Discovery of a Viral NLR Homolog that Inhibits the Inflammasome

Sean M. Gregory,1,2 Beckley K. Davis,1 John A. West,1,2 Debra J. Taxman,1,2 Shu-ichi Matsuzawa,3 John C. Reed,3 Jenny P. Y. Ting,1,2 Blossom Damania1,2,4,*

Abstract: The NLR (nucleotide binding and oligomerization, leucine-rich repeat) family of proteins senses microbial infections and activates the inflammasome, a multiprotein complex that promotes microbial clearance. Kaposi’s sarcoma–associated herpesvirus (KSHV) is linked to several human malignancies. We found that KSHV Orf63 is a viral homolog of human NLRP1. Orf63 blocked NLRP1-dependent innate immune responses, including caspase-1 activation and processing of interleukins IL-1β and IL-18. KSHV Orf63 interacted with NLRP1, NLRP3, and NOD2. Inhibition of Orf63 expression resulted in increased expression of IL-1β during the KSHV life cycle. Furthermore, inhibition of NLRP1 was necessary for efficient reactivation and generation of progeny virus. The viral homolog subverts the function of cellular NLRs, which suggests that modulation of NLR-mediated innate immunity is important for the lifelong persistence of herpesviruses.

1 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
2 Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
3 Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
4 UNC Center for AIDS Research, University of North Carolina, Chapel Hill, NC 27599, USA.

* To whom correspondence should be addressed. E-mail: damania{at}med.unc.edu


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Oxidative metabolism enables Salmonella evasion of the NLRP3 inflammasome.
M. A. Wynosky-Dolfi, A. G. Snyder, N. H. Philip, P. J. Doonan, M. C. Poffenberger, D. Avizonis, E. E. Zwack, A. M. Riblett, B. Hu, T. Strowig, et al. (2014)
J. Exp. Med. 211, 653-668
   Abstract »    Full Text »    PDF »
O-GlcNAc transferase inhibits KSHV propagation and modifies replication relevant viral proteins as detected by systematic O-GlcNAcylation analysis.
R. Jochmann, J. Pfannstiel, P. Chudasama, E. Kuhn, A. Konrad, and M. Sturzl (2013)
Glycobiology 23, 1114-1130
   Abstract »    Full Text »    PDF »
Constitutive Interferon-Inducible Protein 16-Inflammasome Activation during Epstein-Barr Virus Latency I, II, and III in B and Epithelial Cells.
M. A. Ansari, V. V. Singh, S. Dutta, M. V. Veettil, D. Dutta, L. Chikoti, J. Lu, D. Everly, and B. Chandran (2013)
J. Virol. 87, 8606-8623
   Abstract »    Full Text »    PDF »
Regulation of Viral and Cellular Gene Expression by Kaposi's Sarcoma-Associated Herpesvirus Polyadenylated Nuclear RNA.
C. C. Rossetto, M. Tarrant-Elorza, S. Verma, P. Purushothaman, and G. S. Pari (2013)
J. Virol. 87, 5540-5553
   Abstract »    Full Text »    PDF »
Vaccinia virus F1L protein promotes virulence by inhibiting inflammasome activation.
M. Gerlic, B. Faustin, A. Postigo, E. C.-W. Yu, M. Proell, N. Gombosuren, M. Krajewska, R. Flynn, M. Croft, M. Way, et al. (2013)
PNAS 110, 7808-7813
   Abstract »    Full Text »    PDF »
Kaposi's Sarcoma-Associated Herpesvirus Latency in Endothelial and B Cells Activates Gamma Interferon-Inducible Protein 16-Mediated Inflammasomes.
V. V. Singh, N. Kerur, V. Bottero, S. Dutta, S. Chakraborty, M. A. Ansari, N. Paudel, L. Chikoti, and B. Chandran (2013)
J. Virol. 87, 4417-4431
   Abstract »    Full Text »    PDF »
NLRP1 and NLRP3 inflammasomes are essential for distinct outcomes of decreased cytokines but enhanced bacterial killing upon chronic Nod2 stimulation.
M. Hedl and C. Abraham (2013)
Am J Physiol Gastrointest Liver Physiol 304, G583-G596
   Abstract »    Full Text »    PDF »
Inflammasomes and viruses: cellular defence versus viral offence.
A. M. Gram, J. Frenkel, and M. E. Ressing (2012)
J. Gen. Virol. 93, 2063-2075
   Abstract »    Full Text »    PDF »
Porphyromonas gingivalis Mediates Inflammasome Repression in Polymicrobial Cultures through a Novel Mechanism Involving Reduced Endocytosis.
D. J. Taxman, K. V. Swanson, P. M. Broglie, H. Wen, E. Holley-Guthrie, M. T.-H. Huang, J. B. Callaway, T. K. Eitas, J. A. Duncan, and J. P. Y. Ting (2012)
J. Biol. Chem. 287, 32791-32799
   Abstract »    Full Text »    PDF »
NLRs, inflammasomes, and viral infection.
S. R. Jacobs and B. Damania (2012)
J. Leukoc. Biol. 92, 469-477
   Abstract »    Full Text »    PDF »
Tiled Microarray Identification of Novel Viral Transcript Structures and Distinct Transcriptional Profiles during Two Modes of Productive Murine Gammaherpesvirus 68 Infection.
B. Y. H. Cheng, J. Zhi, A. Santana, S. Khan, E. Salinas, J. C. Forrest, Y. Zheng, S. Jaggi, J. Leatherwood, and L. T. Krug (2012)
J. Virol. 86, 4340-4357
   Abstract »    Full Text »    PDF »
Genome-Wide Association Study among Four Horse Breeds Identifies a Common Haplotype Associated with In Vitro CD3+ T Cell Susceptibility/Resistance to Equine Arteritis Virus Infection.
Y. Y. Go, E. Bailey, D. G. Cook, S. J. Coleman, J. N. MacLeod, K.-C. Chen, P. J. Timoney, and U. B. R. Balasuriya (2011)
J. Virol. 85, 13174-13184
   Abstract »    Full Text »    PDF »
Differentially regulated splice variants and systems biology analysis of Kaposi's sarcoma-associated herpesvirus-infected lymphatic endothelial cells.
T.-Y. Chang, Y.-H. Wu, C.-C. Cheng, and H.-W. Wang (2011)
Nucleic Acids Res. 39, 6970-6985
   Abstract »    Full Text »    PDF »
Modulation of Inflammasome Pathways by Bacterial and Viral Pathogens.
M. Lamkanfi and V. M. Dixit (2011)
J. Immunol. 187, 597-602
   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