Cellular pyrin domain-only protein 2 is a candidate regulator of inflammasome activation.
Pyrin domain (PYD) proteins have recently emerged as important signaling molecules involved in the development of innate immunity against intracellular pathogens through activation of inflammatory mediator pathways. ASC is the central adaptor protein, which links pathogen recognition by PYD-containing pathogen recognition receptors, known as PYD-Nod-like receptors (NLR), PAN, PYPAF, NALP, Nod, and Caterpiller proteins, to the activation of downstream effectors, including activation of caspase-1 and NF-kappaB. Activation of these effectors occurs when specific protein complexes, known as inflammasomes, are formed. PYD signal transduction leads to inflammasome assembly and activation of specific effector proteins. It is modulated by a cellular PYD-only protein (cPOP1), which binds to ASC and interferes with the recruitment of ASC to activated PYD-NLRs. Here we describe the identification and characterization of a second cellular POP (cPOP2), which shows highest homology to the PYD of PAN1. cPOP2 binds to ASC and PAN1, thereby blocking formation of cryopyrin and PAN1-containing inflammasomes, activation of caspase-1, and subsequent processing and secretion of bioactive interleukin-1beta. Existence of a second cPOP provides additional insights into inflammasome formation and suggests that POPs might be a common regulatory mechanism to "fine-tune" the activity of specific PYD-NLR family protein-containing inflammasomes.
Dorfleutner
Andrea
A
Mary Babb Randolph Cancer Center and Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, 2826 MBRCC, 1 Medical Center Drive, Morgantown, WV 26506-9300, USA.
Bryan
Nicole B
NB
Talbott
Siera J
SJ
Funya
Kristin N
KN
Rellick
Stephanie L
SL
Reed
John C
JC
Shi
Xianglin
X
Rojanasakul
Yon
Y
Flynn
Daniel C
DC
Stehlik
Christian
C
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism; D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000071198:Pyrin; D014157:Transcription Factors / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; C489780:CNOT8 protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D018836:Inflammation Mediators; D053583:Interleukin-1beta; C000604192:MEFV protein, human; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C495732:NLRP2 protein, human; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D000071198:Pyrin; D014157:Transcription Factors