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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

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