T lymphocyte (T cell) activation and proliferation is induced by the activation of multiple signal transduction pathways. Earlier studies indicate that CARMA1, a Caspase Recruitment Domain (CARD) and Membrane-associated GUanylate Kinase domain (MAGUK)-containing scaffold protein, plays an essential role in NF-κB activation induced by the costimulation of T cell receptor (TCR) and CD28 molecules. However, the molecular mechanism by which CARMA1 mediates TCR-CD28 costimulation-induced NF-κB activation is not fully understood. Here we show that CARMA1 is constitutively oligomerized. This oligomerization of CARMA1 is through its Coiled-coil domain. Disruption of the predicted structure of the Coiled-coil domain of CARMA1 impaired its oligomerization and, importantly, abrogated CARMA1-mediated NF-κB activation. Interestingly, disruption of the CC1 domain abrogates CARMA1 localization, whereas disruption of the CC2 domain seems to inhibit CARMA1 self-association. Together, our results demonstrate that the oligomerization of CARMA1 is required for TCR-induced NF-κB activation. T lymphocyte (T cell) activation and proliferation is induced by the activation of multiple signal transduction pathways. Earlier studies indicate that CARMA1, a Caspase Recruitment Domain (CARD) and Membrane-associated GUanylate Kinase domain (MAGUK)-containing scaffold protein, plays an essential role in NF-κB activation induced by the costimulation of T cell receptor (TCR) and CD28 molecules. However, the molecular mechanism by which CARMA1 mediates TCR-CD28 costimulation-induced NF-κB activation is not fully understood. Here we show that CARMA1 is constitutively oligomerized. This oligomerization of CARMA1 is through its Coiled-coil domain. Disruption of the predicted structure of the Coiled-coil domain of CARMA1 impaired its oligomerization and, importantly, abrogated CARMA1-mediated NF-κB activation. Interestingly, disruption of the CC1 domain abrogates CARMA1 localization, whereas disruption of the CC2 domain seems to inhibit CARMA1 self-association. Together, our results demonstrate that the oligomerization of CARMA1 is required for TCR-induced NF-κB activation. T cell activation and proliferation is induced by major histo-compatibility complex molecules of antigen-presenting cells presenting antigen peptides to T cell receptors (TCR) 2The abbreviations used are: TCR, T cell receptor; CARD, caspase recruitment domain; Bcl10, B cell lymphoma 10; Malt1, mucosa-associated lymphoid tissue protein-1; CC, Coiled-coil; HA, hemagglutinin; WT, wild type; GFP, green fluorescent protein; JNK, c-Jun N-terminal kinase; ERK, extracellular signal-regulated kinase; HEK, human embryonic kidney; PMA, phorbol 12-myristate 13-acetate; EMSA, electrophoretic mobility shift assay. 2The abbreviations used are: TCR, T cell receptor; CARD, caspase recruitment domain; Bcl10, B cell lymphoma 10; Malt1, mucosa-associated lymphoid tissue protein-1; CC, Coiled-coil; HA, hemagglutinin; WT, wild type; GFP, green fluorescent protein; JNK, c-Jun N-terminal kinase; ERK, extracellular signal-regulated kinase; HEK, human embryonic kidney; PMA, phorbol 12-myristate 13-acetate; EMSA, electrophoretic mobility shift assay. on the surface of T cells and a second costimulatory signal generated through interaction of B7 molecules on antigen-presenting cells and CD28 receptors on T cells. This combined stimulation of TCR/CD3 and CD28 molecules (known as CD3-CD28 costimulation) induces a series of signal transduction pathways leading to activation of cytosolic tyrosine kinases, various adaptor proteins, small GTPases, serine/threonine kinases, and phospholipase. These signaling pathways activate several transcription factors, including NF-κB, AP-1, and NF-AT, which ultimately control the production of various cytokines, leading to T cell activation and proliferation. NF-κB is one of the key transcriptional factors activated by TCR engagement. TCR-induced NF-κB activation plays important roles for the proliferation, differentiation, and survival of T cells (1Hayden M.S. Ghosh S. Genes Dev. 2004; 18: 2195-2224Crossref PubMed Scopus (3358) Google Scholar). Stimulation of T cells by antigen-presenting cells induces the formation of a large multicomponent complex at the contact area between the T cell and the antigen-presenting cell, termed the supramolecular activation complex (SMAC) or immunological synapse (IS) (2Dustin M.L. Olszowy M.W. Holdorf A.D. Li J. Bromley S. Desai N. Widder P. Rosenberger F. van der Merwe P.A. Allen P.M. Shaw A.S. Cell. 1998; 94: 667-677Abstract Full Text Full Text PDF PubMed Scopus (586) Google Scholar). The SMAC/IS of a T cell is highly enriched in cholesterol and glycosphingolipids, also termed lipid rafts. Some signaling molecules are constitutively associated with lipid rafts, whereas others are recruited into lipid rafts following CD3-CD28 costimulation (3Bromley S.K. Burack W.R. Johnson K.G. Somersalo K. Sims T.N. Sumen C. Davis M.M. Shaw A.S. Allen P.M. Dustin M.L. Annu. Rev. Immunol. 2001; 19: 375-396Crossref PubMed Scopus (746) Google Scholar). Although it is not fully understood how signaling pathways induced by CD3-CD28 costimulation lead to the activation of NF-κB, recent studies from our group and others have demonstrated that CARMA1, a scaffold molecule, plays an essential role for CD3-CD28 costimulation-induced NF-κB activation (4Lin X. Wang D. Semin. Immunol. 2004; 16: 429-435Crossref PubMed Scopus (86) Google Scholar, 5Gaide O. Favier B. Legler D.F. Bonnet D. Brissoni B. Valitutti S. Bron C. Tschopp J. Thome M. Nat. Immunol. 2002; 3: 836-843Crossref PubMed Scopus (292) Google Scholar, 6Wang D. You Y. Case S.M. McAllister-Lucas L.M. Wang L. DiStefano P.S. Nunez G. Bertin J. Lin X. Nat. Immunol. 2002; 3: 830-835Crossref PubMed Scopus (252) Google Scholar). CARMA1 is a scaffold molecule containing an N-terminal CAspase Recruitment Domain (CARD), a Coiled-coil (C-C) domain, a PDZ domain, a Src homology 3 domain, and a C-terminal guanylate kinase-like (GUK) domain and is a member of the Membrane-associated GUK (MAGUK) family of proteins (7Bertin J. Wang L. Guo Y. Jacobson M.D. Poyet J.L. Srinivasula S.M. Merriam S. DiStefano P.S. Alnemri E.S. J. Biol. Chem. 2001; 276: 11877-11882Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 8Gaide O. Martinon F. Micheau O. Bonnet D. Thome M. Tschopp J. FEBS Lett. 2001; 496: 121-127Crossref PubMed Scopus (169) Google Scholar). Consistent with the roles of MAGUK family proteins, CARMA1 is constitutively associated with the cytoplasmic membrane and is recruited into the immunological synapse following CD3-CD28 costimulation (5Gaide O. Favier B. Legler D.F. Bonnet D. Brissoni B. Valitutti S. Bron C. Tschopp J. Thome M. Nat. Immunol. 2002; 3: 836-843Crossref PubMed Scopus (292) Google Scholar, 6Wang D. You Y. Case S.M. McAllister-Lucas L.M. Wang L. DiStefano P.S. Nunez G. Bertin J. Lin X. Nat. Immunol. 2002; 3: 830-835Crossref PubMed Scopus (252) Google Scholar). Biochemical and gene-targeting studies have confirmed that CARMA1 is required for TCR-induced IκB kinase (IKK) activation and functions downstream of protein kinase C θ (6Wang D. You Y. Case S.M. McAllister-Lucas L.M. Wang L. DiStefano P.S. Nunez G. Bertin J. Lin X. Nat. Immunol. 2002; 3: 830-835Crossref PubMed Scopus (252) Google Scholar, 9Egawa T. Albrecht B. Favier B. Sunshine M. Mirchandani K. O'Brien W. Thome M. Littman D. Curr. Biol. 2003; 13: 1252-1258Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 10Newton K. Dixit V. Curr. Biol. 2003; 13: 1247-1251Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). More recent studies suggest that protein kinase C θ and protein kinase B β phosphorylate CARMA1 in T and B cells, respectively (11Matsumoto R. Wang D. Blonska M. Li H. Kobayashi M. Pappu B. Chen Y. Wang D. Lin X. Immunity. 2005; 23: 575-585Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 12Sommer K. Guo B. Pomerantz J.L. Bandaranayake A.D. Moreno-Garcia M.E. Ovechkina Y.L. Rawlings D.J. Immunity. 2005; 23: 561-574Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar). This phosphorylation likely induces conformational changes in CARMA1, which recruits downstream signaling components Bcl10 (B Cell Lymphoma-10) and MALT1 (mucosa-associated lymphoid tissue protein-1, also known as human paracaspase) to the immunological synapse (9Egawa T. Albrecht B. Favier B. Sunshine M. Mirchandani K. O'Brien W. Thome M. Littman D. Curr. Biol. 2003; 13: 1252-1258Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 10Newton K. Dixit V. Curr. Biol. 2003; 13: 1247-1251Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 13Che T. You Y. Wang D. Tanner M.J. Dixit V.M. Lin X. J. Biol. Chem. 2004; 279: 15870-15876Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 14Wang D. Matsumoto R. You Y. Che T. Lin X. Gaffen S. Lin X. Mol. Cell. Biol. 2004; 24: 164-171Crossref PubMed Scopus (179) Google Scholar). Genetic studies also demonstrate that Bcl10 and MALT1 are required for antigen receptor-induced NF-κB activation (15Ruland J. Duncan G.S. Wakeham A. Mak T.W. Immunity. 2003; 19: 749-758Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar, 16Ruland J. Duncan G.S. Elia A. del Barco Barrantes I. Nguyen L. Plyte S. Millar D.G. Bouchard D. Wakeham A. Ohashi P.S. Mak T.W. Cell. 2001; 104: 33-42Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar, 17Ruefli-Brasse A.A. French D.M. Dixit V.M. Science. 2003; 302: 1581-1584Crossref PubMed Scopus (303) Google Scholar, 18Xue L. Morris S.W. Orihuela C. Tuomanen E. Cui X. Wen R. Wang D. Nat. Immunol. 2003; 4: 857-865Crossref PubMed Scopus (158) Google Scholar). It has been suggested that oligomerization of Bcl10 regulates MALT1 and TRAF6, two potential ubiquitin-protein isopeptide ligase ubiquitination ligases (E3), leading to NEMO (NF-κB essential modulator) ubiquitination (19Zhou H. Wertz I. O'Rourke K. Ultsch M. Seshagiri S. Eby M. Xiao W. Dixit V.M. Nature. 2004; 427: 167-171Crossref PubMed Scopus (451) Google Scholar, 20Sun L. Deng L. Ea C.K. Xia Z.P. Chen Z.J. Mol. Cell. 2004; 14: 289-301Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar). However, how CARMA1 induces Bcl10 oligomerization remains to be determined. Although it has also been proposed that the stimulation of antigen receptors induces oligomerization of CARMA1 (21Rawlings D.J. Sommer K. Moreno-Garcia M.E. Nat. Rev. Immunol. 2006; 6: 799-812Crossref PubMed Scopus (153) Google Scholar, 22Schulze-Luehrmann J. Ghosh S. Immunity. 2006; 25: 701-715Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar), there is no direct evidence showing that the oligomerization of CARMA1 is functionally important. In this study, we demonstrated that CARMA1 could indeed form oligomers and, importantly, that this oligomerization was required for TCR-induced NF-κB activation and disruption of this oligomerization completely inhibited CARMA1-mediated NF-κB activation. Furthermore, domain mapping of the CC domain shows different regions contribute to membrane localization and oligomerization. Thus, our studies provide biochemical evidence that oligomerization and localization of CARMA1 play an essential role in TCR-induced NF-κB activation. Yeast Two-hybrid Screening—Yeast two-hybrid interaction assays were performed in yeast strain AH109 transfected by the standard lithium acetate method (Clontech). A human lymph node cDNA library was used (Clontech). Screening plasmids were generated by inserting the CARD+CC domains of CARMA1 in-frame with the GAL4 DNA-binding domain in the pGBKT7 vector (Clontech). Screening was performed at high stringency as described in the manufacturer's instructions. Positive clones were screened for β-galactosidase activity and sequenced. Further confirmatory yeast two-hybrid experiments used high stringency plate agar. Plasmids and Antibodies—Plasmids encoding Myc- and FLAG epitope-tagged CARMA1 were described previously (14Wang D. Matsumoto R. You Y. Che T. Lin X. Gaffen S. Lin X. Mol. Cell. Biol. 2004; 24: 164-171Crossref PubMed Scopus (179) Google Scholar). CARMA1 point mutants were generated using site-directed mutagenesis and confirmed by sequencing analysis. These mutants were inserted into pCMVTag2B (FLAG), pRK6 (Myc or HA), or lentiviral vector pRV (Myc or HA) plasmids. Mouse full-length WT and L298Q CARMA1 expression plasmids were kindly provided by C. C. Goodnow (23Jun J. Wilson L. Vinuesa C. Lesage S. Blery M. Miosge L. Cook M. Kucharska E. Hara H. Penninger J. Domashenz H. Hong N. Glynne R. Nelms K. Goodnow C. Immunity. 2003; 18: 751-762Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar). Antibodies for c-Myc, HA, and green fluorescent protein (GFP) were from Santa Cruz Biotechnology; antibodies for p-JNK, JNK, Bcl10, p-ERK, ERK, and MALT1 were from Cell Signaling, Inc.; antibodies for FLAG (M2) were from Sigma Co.; and antibodies for CARMA1 were from Axxora Life Science Inc. Cell Culture and Stimulation—Jurkat E6.1, JPM50.6 (6Wang D. You Y. Case S.M. McAllister-Lucas L.M. Wang L. DiStefano P.S. Nunez G. Bertin J. Lin X. Nat. Immunol. 2002; 3: 830-835Crossref PubMed Scopus (252) Google Scholar), and Raji cells were cultured in RPMI1640 medium supplemented with 10% fetal calf serum at 37 °C in 5% CO2. Human embryonic kidney (HEK) 293T cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% fetal calf serum at 37 °C in 5% CO2. Costimulation of Jurkat cells (1 × 107) was performed in a final volume of 1 ml by addition of anti-CD3 (5 μg/ml) and anti-CD28 (3 μg/ml) antibodies, with goat anti-mouse (3 μg/ml) (Signal Transduction Laboratories). Additional stimulations include phorbol 12-myristate 13-acetate (PMA) (10 ng/ml), ionomycin (100 ng/ml), and 20 ng of TNFα. Luciferase Reporter Assay—JPM50.6 cells (1 × 107 in 0.4 ml of RPMI1640 medium) were electroporated with 5 μg of NF-κB-dependent luciferase (firefly) reporter plasmid and 100 ng of EF1α promoter-dependent Renilla luciferase plasmid together with 10 μg of expression vectors of CARMA1 and its CC mutants or vector controls. After a 16-h incubation, the cells were stimulated with or without anti-CD3 (5 μg/ml) and anti-CD28 (3 μg/ml) antibodies or (10 anti-CD28 (3 μg/ml) antibodies for Luciferase in the cell were by the cell luciferase were with × cells and transfected with 100 ng of NF-κB-dependent luciferase (firefly) reporter plasmid and 1 ng of EF1α promoter-dependent Renilla luciferase plasmid together with μg of expression vectors of CARMA1 or Cell or JPM50.6 cells were transfected at with 20 μg of plasmid cell were with or medium by were for expression to the of an transduction was also used to cell with vectors containing different CARMA1 cells were in and transfected with 5 μg of for of 10 μg of or WT or CARMA1 by After was and with RPMI1640 After an medium was and with × Jurkat or JPM50.6 cells. were and expression was by with were from different cells various (1 × 107) were in 100 of (10 10 1 and were for biochemical analysis. were in of and in of 0.4 1 and After for at the were and the proteins in the were were by protein using serum was performed with 10 μg of and NF-κB or Cell T cells WT, or were with B at °C for 20 were and in RPMI1640 at Raji B cells were with or without μg of ml at 37 °C for Raji cells were with an volume of Jurkat cells, in and to by was on an were transfected into cells by After 16-h of incubation, proteins were with various antibodies and were with 1 and and with The were to and CARMA1 the molecular mechanism by which the of CARMA1 is we performed a yeast two-hybrid using the of CARMA1 and CC as the a human lymph node cDNA clones were and sequenced. of the clones an N-terminal CARMA1 in which the N-terminal domain was a of the CC domain as as the MAGUK domain. This that CARMA1 this several were into the yeast two-hybrid and for interaction that the was to This was to with the CARMA1 CC domain, not with the domain. Furthermore, two CC domains were interaction Together, results indicate that CARMA1 form a through its CC two-hybrid CARMA1 in a Mouse and human CC domains could with not that the is a of and human Although the formation of a has been in CC proteins, the this In a known CC was of that the L298Q of CARMA1 signaling (23Jun J. Wilson L. Vinuesa C. Lesage S. Blery M. Miosge L. Cook M. Kucharska E. Hara H. Penninger J. Domashenz H. Hong N. Glynne R. Nelms K. Goodnow C. Immunity. 2003; 18: 751-762Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar). Together, results indicate that CARMA1 form a or through its domain and that the CARMA1 CC is and for this oligomerization. CARMA1 in cells, an was vectors encoding Myc- and CARMA1 proteins were transfected into cells. After cells were and to Consistent with the we that was to with whereas which also a CC domain, was to with to oligomerization is a family a of CARMA1 with different tissue was for its to form oligomers L. N. P. J. A. Li Chen S. Chen F. S. I. Mak T. Nunez G. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). that could as as with CARMA1 These results suggest that CARMA1 and in a in signal transduction pathways. Earlier studies indicate that functionally cells (11Matsumoto R. Wang D. Blonska M. Li H. Kobayashi M. Pappu B. Chen Y. Wang D. Lin X. Immunity. 2005; 23: 575-585Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar). Together, indicate that the CARMA1 protein is into a the oligomerization of CARMA1 in T cells and this changes cell with cells were with or without a encoding an CARMA1 and stimulated with or without CD3-CD28 for or 20 were to with antibodies and for and epitope-tagged in the of CARMA1 oligomerization not This that stimulation not CARMA1 oligomerization and CARMA1 is of its activation Stimulation was confirmed by of a Coiled-coil the of CARMA1 the structure of the CARMA1 CC domain was and E. P.S. B. 6: PubMed Scopus Google Scholar), we predicted that CARMA1 and contribute to the between CC domains The indicate regions of potential Coiled-coil formation at that two Coiled-coil domains together are of predicted CARMA1 mutants with including and were generated by site-directed a CARMA1 was with the in are from that show regions of predicted Coiled-coil formation E. P.S. B. 6: PubMed Scopus Google Scholar). After of Coiled-coil formation were E. P.S. B. 6: PubMed Scopus Google Scholar). of Coiled-coil of the oligomerization of CARMA1, and WT, or of CARMA1 were into JPM50.6 cells Jurkat T the cells wild CARMA1 as as WT or mutants of that was with and to a with and not with These results indicate that CARMA1 is in and that in the CARMA1 CC domain its oligomerization. Furthermore, the CC2 of CARMA1 to be in CARMA1 oligomerization the CC1 regions to contribute to of the of CARMA1 in the CC domain CARMA1 we JPM50.6 cells by lentiviral in which or were These cell were by for to the TCR-induced NF-κB Although wild CARMA1 could the NF-κB in cells, we that CC could not CD3-CD28 or NF-κB activation of and its mutants were in cells The show of Consistent with results (6Wang D. You Y. Case S.M. McAllister-Lucas L.M. Wang L. DiStefano P.S. Nunez G. Bertin J. Lin X. Nat. Immunol. 2002; 3: 830-835Crossref PubMed Scopus (252) Google Scholar), CARMA1 no on NF-κB activation In we activation induced by stimulations and that was activated by stimulation in cells the signaling downstream of CARMA1, wild and of CARMA1 were for to activate the NF-κB downstream of the is in activation of downstream signaling we transfected expression plasmids encoding wild or of CARMA1 with an NF-κB-dependent luciferase reporter into cells. that and could activate the NF-κB luciferase reporter This that the downstream of CARMA1 is not by a of CARMA1 self-association. the not downstream signaling leading to NF-κB activation. with Bcl10 and MALT1 cells or were stimulated with or without CARMA1 proteins were from stimulated and and the of Bcl10 and MALT1 was in stimulated not Together, indicate that in the CC domain not the of CARMA1 to with downstream signaling The the oligomerization of CARMA1, in a signaling at the of CARMA1, which functionally into the TCR signaling of a Coiled-coil domain. The CC1 CARMA1 of the CC domain of CARMA1 the localization of CARMA1, we the localization of WT, and of Jurkat T cells CARMA1 WT and mutants were These cells and were used in a cell to the of CC domain on localization to the immunological synapse antigen cells were with which with and lipid rafts. These cells were with Raji B cells with or without E. Cell were for the of and lipid rafts by B. In cells, CARMA1 was cells we that CARMA1 WT and were at the cell whereas stimulation not or to the lipid domain These results indicate that in the CC1 domain of CARMA1 its localization, that the CC1 is in the localization of CARMA1, the shows localization whereas shows of the Coiled-coil the in the CC1 and CC2 regions NF-κB activation it is that regions could as a in TCR A Jurkat cell that was used to an in expression in cells activation of NF-κB, in to Jurkat cells. In an to the of interaction between CARMA1 Jurkat cells were transfected with or expression plasmids together with an NF-κB-dependent luciferase and a luciferase was performed with that expression of small of CARMA1 inhibited NF-κB activation The CC1 inhibited NF-κB activation by and the CC2 inhibited NF-κB activation by the of signaling between A complex of is for the transduction of TCR signaling to activate expression for the of an Earlier studies have demonstrated that CARMA1 plays an essential role in TCR-induced NF-κB activation. In this study, we demonstrate that CARMA1 as a in T cells. The oligomerization of CARMA1 is through its Coiled-coil domain. our results indicate that CC domain mutants the of not on cell that TCR signaling the of CARMA1 with proteins not CARMA1 oligomerization. our studies provide biochemical and evidence that the oligomerization of CARMA1 is required for TCR-induced NF-κB activation. It has been CARMA1 recruits signaling components as Bcl10, and of complex into the immunological synapse T. You Y. Wang D. Tanner M.J. Dixit V.M. Lin X. J. Biol. Chem. 2004; 279: 15870-15876Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 14Wang D. Matsumoto R. You Y. Che T. Lin X. Gaffen S. Lin X. Mol. Cell. Biol. 2004; 24: 164-171Crossref PubMed Scopus (179) Google Scholar, H. C. T. Bouchard D. R. T. Penninger J. 2004; PubMed Scopus Google Scholar). localization of CARMA1 is required for TCR-induced NF-κB activation. Interestingly, is to with Bcl10 and MALT1 downstream components were not It seems the formation and the signal transduction through the studies suggest that the C-terminal MAGUK domain of CARMA1 to the localization of CARMA1 (11Matsumoto R. Wang D. Blonska M. Li H. Kobayashi M. Pappu B. Chen Y. Wang D. Lin X. Immunity. 2005; 23: 575-585Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 14Wang D. Matsumoto R. You Y. Che T. Lin X. Gaffen S. Lin X. Mol. Cell. Biol. 2004; 24: 164-171Crossref PubMed Scopus (179) Google Scholar). In this study, we that of the CC1 domain of CARMA1 also impaired its localization, that the CC domain of CARMA1 also contribute to its Although our results suggest that the CC1 and CC2 regions are required for it that the CC1 to the localization of The a key interaction between CARMA1 and an that CARMA1 to the immunological Although is at the of the CC1 it is that the of the L298Q in CARMA1, in (23Jun J. Wilson L. Vinuesa C. Lesage S. Blery M. Miosge L. Cook M. Kucharska E. Hara H. Penninger J. Domashenz H. Hong N. Glynne R. Nelms K. Goodnow C. Immunity. 2003; 18: 751-762Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar), also be to the of the localization of the CC2 a on NF-κB it is likely that this small the of CARMA1 and inhibit TCR-induced NF-κB activation. The likely as a by two full-length CARMA1 proteins from which abrogates this oligomerization be a for antigen receptor-induced NF-κB activation. A small the CARMA1 CC2 could as an for lymphocyte activation. for
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