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PMID: 21252346 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Discovery of a viral NLR homolog that inhibits the inflammasome.

Science (New York, N.Y.) ·Vol. 331 ·No. 6015 ·2011-01-21 ·Pages 330-4

Gregory SM, Davis BK, West JA, Taxman DJ, Matsuzawa S, Reed JC, Ting JP, Damania B

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.

MeSH Terms
Adaptor Proteins, Signal Transducing/antagonists & inhibitors,chemistry,genetics,metabolism Amino Acid Sequence Apoptosis Apoptosis Regulatory Proteins/antagonists & inhibitors,chemistry,genetics,metabolism Carrier Proteins/metabolism Caspase 1/metabolism Caspase Inhibitors Cell Line Cell Line, Tumor Herpesvirus 8, Human/genetics,immunology,physiology Humans Immune Evasion Immunity, Innate Inflammasomes/antagonists & inhibitors,metabolism Interleukin-1beta/metabolism Molecular Sequence Data Monocytes/virology NLR Family, Pyrin Domain-Containing 3 Protein NLR Proteins Nod2 Signaling Adaptor Protein/metabolism Protein Binding Protein Interaction Domains and Motifs Transfection Viral Proteins/chemistry,genetics,metabolism Virus Activation Virus Latency Virus Replication
Chemicals
Adaptor Proteins, Signal Transducing Apoptosis Regulatory Proteins Carrier Proteins Caspase Inhibitors Inflammasomes Interleukin-1beta NLR Family, Pyrin Domain-Containing 3 Protein NLR Proteins NLRP1 protein, human NLRP3 protein, human NOD2 protein, human Nod2 Signaling Adaptor Protein Orf63 protein, Kaposi's sarcoma-associated herpesvirus Viral Proteins Caspase 1
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Gregory Sean M
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Davis Beckley K
West John A
Taxman Debra J
Matsuzawa Shu-ichi
Reed John C
Ting Jenny P Y
Damania Blossom
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1199478
Published
2011-01-21
Pages
330-4
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC3072027
Subset
IM
Grants
NCI NIH HHS · R01 CA156330 · United States
NIAID NIH HHS · F32-AI78735 · United States
NCI NIH HHS · 5R21CA131645 · United States
NIAID NIH HHS · R01 AI091967 · United States
NIAID NIH HHS · AI077437 · United States
NIAID NIH HHS · R01 AI056324 · United States
NIAID NIH HHS · AI56324 · United States
NIAID NIH HHS · AI91967 · United States
NIAID NIH HHS · U19 AI077437 · United States
NCI NIH HHS · R01 CA096500-10 · United States
NIAID NIH HHS · U54 AI057157 · United States
NIAID NIH HHS · T32 AI007001 · United States
NIAID NIH HHS · T32 AI007419 · United States
NCI NIH HHS · R21 CA131645 · United States
NCI NIH HHS · CA096500 · United States
NIAID NIH HHS · AI057157 · United States
NIDCR NIH HHS · DE018281 · United States
NCI NIH HHS · CA156330 · United States
NIAID NIH HHS · T32-AI007419 · United States
NIAID NIH HHS · T32-AI007001 · United States
NIDCR NIH HHS · R01 DE018281-05 · United States
NIDCR NIH HHS · R01 DE018281 · United States
NIAID NIH HHS · F32 AI078735 · United States
NCI NIH HHS · R01 CA096500 · United States
Corrections
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PMID: 21451560
External Links
PubMed source DOI: 10.1126/science.1199478 PMC Full Text View journal details
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