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Disrupts ASC:CLR Interactions B and Κ Pyrin-Only Protein 2 Modulates Pyrin-Only Protein 2 Modulates NF-κB and Disrupts ASC:CLR Interactions Felipe Bedoya, Laurel L. Sandler and Jonathan A. Harton This information is current as J Immunol 2007; 178:3837-3845; ; of September 23, 2021. doi: 10.4049/jimmunol.178.6.3837 http://www.jimmunol.org/content/178/6/3837 Downloaded from References This article cites 59 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/178/6/3837.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 23, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Pyrin-Only Protein 2 Modulates NF-␬B and Disrupts ASC:CLR Interactions Felipe Bedoya,* Laurel L. Sandler,* and Jonathan A. Harton1*† 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 apo- ptosis, 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 Downloaded from 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 Journal of Immunology, 2007, 178: 3837–3845. http://www.jimmunol.org/ ctivation of NF-␬B regulates numerous cellular processes inducible (IFI) genes, coding for the HIN-200 family of hemopoi- including cytokine and adhesion molecule expression, cell etic nuclear proteins, contain one or two copies of a 200-aa pro- A cycle regulation, and cell growth. Accordingly, constitutive tein-protein interaction domain, are preceded by a PYD, and are or excessive NF-␬B activity is observed in inflammatory diseases, likely involved in cell proliferation and differentiation (9, 10). The autoimmunity, and cancer (1, 2). Proteins containing the death domain PYD of apoptosis speck protein containing a CARD, ASC (TMS1/ (DD)2 fold (DDF) are associated with NF-␬B signaling and apoptosis PyCARD), is followed by a CARD domain. ASC associates with induction. Four related protein-protein interaction domains comprise PYD- or CARD-containing proteins through homotypic interac- the DDF superfamily: the DD; the death effector domain; the tions via both domains (11, 12). In proapoptotic cells, ASC as- caspase recruitment domain (CARD); and the pyrin domain sembles in large multimeric perinuclear complexes or “specks” by by guest on September 23, 2021 (PYD). These domains share a similar tertiary structure, a five to interacting with PYD-containing proteins. The physiological sig- six ␣-helical bundle that likely function as homotypic interaction nificance of these interactions and the speck structure itself re- modules. DDF proteins act as adaptors, recruiting signaling pro- mains unclear. ASC also participates in forming the inflammasome teins into complexes domains, ultimately contributing to apoptosis, complex that processes pro-IL-1␤ into the mature form (13). Two innate immune responses, and cancer development (1–5). thirds of the recently discovered CATERPILLER (CLR) family of Pyrin motifs are generally found at the N terminus of multido- intracellular pathogen receptors encode a PYD followed by a nu- main proteins. Pyrin (marenostrin), the founding family member, cleotide binding domain and leucine-rich repeats domain (14, 15). is associated with familial Mediterranean fever, an autosomal re- CLR proteins mediate innate immune responses to certain bacterial cessive disease characterized by sporadic attacks of fever and in- products, are involved in autoinflammatory diseases, and may pro- flammation with intense abdominal, joint, and chest pain (6, 7). mote apoptosis (15). Some PYD-containing proteins of the CLR Pyrin also contains a B-box zinc finger and a SPRY domain func- family induce NF-␬B activation in conjunction with ASC, includ- tioning as adaptor and ligand binding units, respectively (8). IFN ing PYPAF5, Monarch, and CIAS1/NALP3 (4, 16, 17). Not sur- prisingly, mutations in CIAS1 associated with the inflammatory syndromes familial cold urticaria, Muckle-Wells, and chronic in- *Department of Molecular Medicine, University of South Florida College of Med- fantile neurologic cutaneous articular syndrome, show increased icine, and †Immunology Program, H. Lee Moffitt Cancer Center and Research ␬ Institute, Tampa, FL 33612 capacity for ASC-dependent NF- B activation (18–21). Other CLRs, such as PAN2/PYPAF4 mediate NF-␬B suppression (22). Received for publication April 20, 2006. Accepted for publication December 28, 2006. Although the nucleotide binding domain/leucine-rich repeats do- 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 main of CIAS1 inhibits NF- B nuclear import, the PYD of PAN2/ with 18 U.S.C. Section 1734 solely to indicate this fact. PYPAF4 inhibits NF-␬B, a function likely mediated through the 1 Address correspondence and reprint requests to Dr. Jonathan A. Harton at the cur- I␬B kinase (IKK) complex (22, 23). rent address, Center for Immunology and Microbial Disease, Albany Medical Col- The NF-␬B family of transcription factors is comprised of five lege, 47 New Scotland Avenue, MC-151, Albany, NY 12208. E-mail address: [email protected] members in mammals: p65 (Rel A), Rel B, c-Rel, p50/p105, and ␬ 2 Abbreviations used in this paper: DD, death domain; DDF, DD fold; CARD, p52/p100, existing as homo- or heterodimers bound to the I B caspase recruitment domain; PYD, pyrin domain; IKK, I␬B kinase; POP, pyrin-only inhibitory complex in the cytosol. Upon induction by proinflam- protein; DAPI, 4Ј,6Ј-diamidino-2-phenylindole; NLS, nuclear localization signal se- matory stimuli such as TNF-␣ or LPS, I␬B␣ is phosphorylated by quence; COP, CARD-only protein. the IKK complex, ubiquitinated, and degraded by the 26S pro- Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 teasome. This process unmasks NF-␬B’s nuclear localization www.jimmunol.org 3838 POP2 BLOCKS NF-kB ACTIVITY AND ASC:CLR INTERACTION sequence, leading to its translocation into the nucleus. Binding of clonal IgG was obtained from Santa Cruz Biotechnology, and Alexa Fluor 594 NF-␬B to its cognate DNA response elements induces the tran- goat anti-rabbit IgG (HϩL) was obtained from Molecular Probes. scription of a host of cytokines and growth factors (e.g., IL-2, IL-8, IFN-␤, M-CSF, G-CSF, vascular endothelial growth factor), as Cloning and RT-PCR well as various transcription factors and signaling regulators (e.g., A cDNA encoding POP2 was amplified from total RNA from the B cell I␬B␣ and IFN regulatory factor-1 and -2) (2, 24). The pivotal role line Ramos by RT-PCR using the reverse transcribed One-Step Kit (Qia- of NF-␬B in biological processes modulating the immune response gen) with the primers (forward 5Ј-aaccgcggatggcatcttctgcagag-3Ј and re- suggests that localization and subsequent activation must be rig- verse 5Ј-aaaagcttatggcatcttctgcagag-3Ј) designed to obtain POP2 cDNA orously controlled. Dysregulation of these events contributes to flanked by HindIII and XhoI restrictions sites. Subsequently, POP2 was cloned into the pCDNA 3.1 vector containing an N-terminal Flag or Myc aberrant gene expression associated with numerous human dis- epitope. For POP2 mRNA detection, total RNA was isolated from Daudi, eases including cancer, neurodegenerative disorders, arthritis, and Ramos (B cell lymphomas), Jurkat (human T cell leukemia), THP-1 (hu- chronic inflammation (1, 2). man monocytic cell line), and K562 (human erythroid cell line) using the Solitary PYDs
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