Discovery of a Viral NLR Homolog that Inhibits the Inflammasome

• Published in: Science (American Association for the Advancement of Science) Vol. 331; no. 6015; pp. 330 - 334
• Main Authors: Gregory, Sean M, Davis, Beckley K, West, John A, Taxman, Debra J, Matsuzawa, Shu-ichi, Reed, John C, Ting, Jenny P.Y, Damania, Blossom
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 21.01.2011; The American Association for the Advancement of Science
• Subjects: Activation; Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Amino Acid Sequence; Apoptosis; Apoptosis Regulatory Proteins - antagonists & inhibitors; Apoptosis Regulatory Proteins - chemistry; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Binding; Biological and medical sciences; Blocking; Cancer; Carrier Proteins - metabolism; Caspase 1 - metabolism; Caspase Inhibitors; Cell death; Cell Line; Cell Line, Tumor; Cell lines; Cellular biology; Cellular immunity; Fundamental and applied biological sciences. Psychology; Grants; Herpes viruses; Herpesvirus 8, Human - genetics; Herpesvirus 8, Human - immunology; Herpesvirus 8, Human - physiology; Human; Human herpesvirus 8; Humans; Immune Evasion; Immune system; Immunity, Innate; Infections; Inflammasomes - antagonists & inhibitors; Inflammasomes - metabolism; Inhibition; Interleukin-1beta - metabolism; Kaposi's sarcoma-associated herpesvirus; Microbiology; Microorganisms; Modulation; Molecular Sequence Data; Monocytes; Monocytes - virology; NLR Family, Pyrin Domain-Containing 3 Protein; NLR Proteins; Nod2 Signaling Adaptor Protein - metabolism; Nucleotides; Pattern Recognition; Plasmids; Progeny; Protein Binding; Protein Interaction Domains and Motifs; Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains; Small interfering RNA; Transfection; Vero cells; Viral infections; Viral Proteins - chemistry; Viral Proteins - genetics; Viral Proteins - metabolism; Virology; Virus Activation; Virus Latency; Virus Replication; Gammaherpesvirinae; Virus; Human herpesvirus 8; Inflammasome; Host virus relation; Herpesviridae
• DOI: 10.1126/science.1199478
• ISSN: 0036-8075

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.