Inhibition of the inflammasome response by a viral protein that interacts with NLRs

Abstract

Pattern recognition receptors (PRRs) constitute the first line of host defense against bacterial, fungal and viral pathogens. Upon sensing microbial infection, PRRs initiate a cascade of signal transduction and transcriptional events to induce the production of inflammatory cytokines. As a result, many pathogens have evolved to evade PRR detection and activation in order to establish a successful infection. In a recent report, we described how a viral protein named Orf63 encoded by Kaposi’s sarcoma-associated herpesvirus (KSHV) inhibits activation of several members of a family of PRRs called NLRs (nucleotide-binding and oligomerization, leucine-rich repeat) by functionally inhibiting the NLR response. This resulted in reduced NLR-dependent pro-inflammatory cytokine secretion and cell death. Moreover, Orf63 was essential in the KSHV lifecycle. Thus, our work suggests KSHV has evolved to encode a functional homolog of NLR proteins in an effort to suppress the host inflammatory response. 

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Acknowledgments

We thank Stefanie Mach and John West for critical reading of the manuscript. B.D. is supported by NIH grants CA096500, DE018281, American Heart Association grant 0640041N and a Burroughs Wellcome Fund grant. S.M.G. is supported in part by NIH training grants T32-AI007419 and T32-AI007001. B.D. is a Leukemia & Lymphoma Society Scholar and Burroughs Wellcome Fund Investigator in Infectious Disease.

Figures and Tables

Figure 1 The effect of Orf63 on the formation and activity of the NLRP1 inflammasome. (A) Normal activation of the NLRP1 inflammasome. NLRP1 exists in an autoinhibited state in the absence of pathogen infection where the LRR domain folds back onto the NBD to prevent inflammasome formation. Pathogen detection induces NLRP1 into an open conformation facilitating the association with procaspase-1 through homotypic interactions between CARD domains to form the inflammasome. The association of NLRP1 with procaspase-1 initiates autocatalytic processing of procaspase-1 to catalytically active caspase-1, which cleaves pro-IL-1β and/or IL-18 to their biologically active forms. (B) Orf63 disrupts the interaction of procaspase-1 and NLRP1. Through molecular mimicry of NLRP1's NBD and LRR, Orf63 interacts directly with NLRP1 and blocks NLRP1 inflammasome formation preventing downstream procaspase-1 activation and subsequent IL-1β/IL-18 processing.

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