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B and Disrupts ASC:CLR Interactions
* Department of Molecular Medicine, University of South Florida College of Medicine, and
Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612
NF-
B is pivotal for transactivation of cell-cycle regulatory, cytokine, and adhesion molecule genes and is dysregulated in many cancers, neurodegenerative disorders, and inflammatory diseases. Proteins with pyrin and/or caspase recruitment domains have roles in apoptosis, innate immunity, and inflammation. Many pyrin domain (PYD) proteins modulate NF-B activity as well as participate in assembling both the perinuclear "apoptotic speck" and the pro-IL1
/IL-18-converting inflammasome complex. "Pyrin-only" proteins (POP) are attractive as negative regulators of PYD-mediated functions and one such protein, POP1, has been reported. We report the identification and initial characterization of a second POP. POP2 is a 294 nt single exon gene located on human chromosome 3 encoding a 97-aa protein with sequence and predicted structural similarity to other PYDs. Highly similar to PYDs in CATERPILLER (CLR, NLR, NALP) family proteins, POP2 is less like the prototypic pyrin and ASC PYDs. POP2 is expressed principally in peripheral blood leukocytes and displays both cytoplasmic and nuclear expression patterns in transfected cells. TNF-
-stimulated and p65 (RelA)-induced NF-B-dependent gene transcription is inhibited by POP2 in vitro by a mechanism involving changes in NF-B nuclear import or distribution. While colocalizing with ASC in perinuclear specks, POP2 also inhibits the formation of specks by the CLR protein CIAS1/NALP3. Together, these observations demonstrate that POP2 is a negative regulator of NF-B activity that may influence the assembly of PYD-dependent complexes.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Address correspondence and reprint requests to Dr. Jonathan A. Harton at the current address, Center for Immunology and Microbial Disease, Albany Medical College, 47 New Scotland Avenue, MC-151, Albany, NY 12208. E-mail address: hartonj{at}mail.amc.edu
2 Abbreviations used in this paper: DD, death domain; DDF, DD fold; CARD, caspase recruitment domain; PYD, pyrin domain; IKK, IB kinase; POP, pyrin-only protein; DAPI, 4',6'-diamidino-2-phenylindole; NLS, nuclear localization signal sequence; COP, CARD-only protein.
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