Discovery of a viral NLR homolog that inhibits the inflammasome.
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.
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Sean M
SM
Gregory
Beckley K
BK
Davis
John A
JA
West
Debra J
DJ
Taxman
Shu-ichi
S
Matsuzawa
John C
JC
Reed
Jenny P Y
JP
Ting
Blossom
B
Damania
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors; D002460:Cell Line; D045744:Cell Line, Tumor; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D058847:Inflammasomes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008969:Molecular Sequence Data; D009000:Monocytes / Q000821:virology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D014162:Transfection; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014775:Virus Activation; D017735:Virus Latency; D014779:Virus Replication
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; C427903:NLRP1 protein, human; C453881:NLRP3 protein, human; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C555687:Orf63 protein, Kaposi's sarcoma-associated herpesvirus; D014764:Viral Proteins; D020170:Caspase 1
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