Discovery of a Viral NLR Homolog that Inhibits the Inflammasome

Sean M. Gregory, Beckley K. Davis, John A. West, Debra J. Taxman, Shu-ichi Matsuzawa, John C. Reed, Jenny P. Y. Ting, Blossom Damania

2011. Science 331, 330-334

Speaker: Chun-Yang Lin (林峻暘)                                Time: 14:00~15:00, May. 4, 2011

Commentator: Dr. Pei-Jan Tsai (蔡佩珍博士)              Place: Room 601

Abstract:

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD) (1). Activation of a subset of NLRs (nucleotide binding and oligomerization, leucine-rich repeat) causes the formation of multimeric complexes termed inflammasomes, which regulate the cleavage and activation of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18, as well as host-cell death (2). Previous studies indicate that TLRs (Toll-like receptors) play an important role in the life cycle of KSHV. However, whether NLRs also do so is unknown. By squence analysis, they found that KSHV Orf63 is very homologous to NLRP1. Further, Orf63 expression in THP-1 cells significantly inhibited MDP (muramyldipeptide) induced IL-1b and IL-18 production and protected cells from NLRP1-dependent cell death. Next, coimmunoprecipitation assay showed that Orf63 could interact with NLRP1, rather than ASC (apoptotic-associated specklike) or caspase-1. The interaction between Orf63 and NLRP1 resulted in preventing NLRP1 oligomerization and inhibiting the association of NLRP1 with procaspase-1. Furthermore, using siRNA knockdown of Orf63 in KSHV-infected primary human monocytes led to increase IL-1b expression and decrease viral gene expression. Taken together, Orf63 is capable of inhibiting of NLR inflammasome responses. Targeting of NLR proteins might play a key role in the herpesvirus life cycle. The modulation of NLR-mediated innate immunity is important for the lifelong persistence of herpesviruses.

References:

1.          Coscoy, L. (2007). "Immune evasion by Kaposi's sarcoma-associated herpesvirus." Nat Rev Immunol 7(5): 391-401.

2.          Schroder, K. and J. Tschopp (2010). "The inflammasomes." Cell 140(6): 821-832.