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Infection and Immunity, March 2007, p. 1484-1492, Vol. 75, No. 3
0019-9567/07/$08.00+0     doi:10.1128/IAI.01315-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Cellular Pyrin Domain-Only Protein 2 Is a Candidate Regulator of Inflammasome Activation{triangledown}

Andrea Dorfleutner,1,{dagger} Nicole B. Bryan,1,{dagger} Siera J. Talbott,1 Kristin N. Funya,1 Stephanie L. Rellick,1 John C. Reed,2 Xianglin Shi,3 Yon Rojanasakul,4 Daniel C. Flynn,1 and Christian Stehlik1*

Mary Babb Randolph Cancer Center and Department of Microbiology, Immunology & Cell Biology, West Virginia University School of Medicine, 1 Medical Center Drive, Morgantown, West Virginia 26506-9300,1 Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 92037,2 Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505,3 Department of Pharmaceutical Sciences, West Virginia University School of Pharmacy, 1 Medical Center Drive, Morgantown, West Virginia 26506-95004

Received 15 August 2006/ Returned for modification 23 September 2006/ Accepted 4 December 2006

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-{kappa}B. 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-1ß. 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.

* Corresponding author. Mailing address: Mary Babb Randolph Cancer Center and Department of Microbiology, Immunology & Cell Biology, West Virginia University School of Medicine, 2826 MBRCC, 1 Medical Center Drive, Morgantown, WV 26506-9300. Phone: (304) 293-8785. Fax: (304) 293-4667. E-mail: cstehlik{at}hsc.wvu.edu.

{triangledown} Published ahead of print on 18 December 2006.

Editor: F. C. Fang

{dagger} These authors contributed equally to this work.

Infection and Immunity, March 2007, p. 1484-1492, Vol. 75, No. 3
0019-9567/07/$08.00+0     doi:10.1128/IAI.01315-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bryan, N. B., Dorfleutner, A., Rojanasakul, Y., Stehlik, C. (2009). Activation of Inflammasomes Requires Intracellular Redistribution of the Apoptotic Speck-Like Protein Containing a Caspase Recruitment Domain. J. Immunol. 182: 3173-3182 [Abstract] [Full Text]  
  • Srimathi, T., Robbins, S. L., Dubas, R. L., Chang, H., Cheng, H., Roder, H., Park, Y. C. (2008). Mapping of POP1-binding Site on Pyrin Domain of ASC. J. Biol. Chem. 283: 15390-15398 [Abstract] [Full Text]  
  • Stehlik, C., Dorfleutner, A. (2007). COPs and POPs: Modulators of Inflammasome Activity. J. Immunol. 179: 7993-7998 [Abstract] [Full Text]  


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