Nuclear Tumor Necrosis Factor Receptor-associated Factor 6 in Lymphoid Cells Negatively Regulates c-Myb-mediated Transactivation through Small Ubiquitin-related Modifier-1 Modification

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an adaptor/scaffold protein that mediates several important signaling pathways, including the tumor necrosis factor-R:NF-κB pathway, involved in immune surveillance, inflammation, etc. Because most studies of TRAF6 function have focused primarily on its role as an adaptor molecule in signaling pathways in the cytoplasm, the potential functions of TRAF6 in other cellular compartments has not been previously investigated. Here, we demonstrate that TRAF6 resides not only in the cellular cytoplasm but is also found in the nuclei of both normal and malignant B lymphocytes. TRAF6 does not possess a nuclear localization signal but enters the nucleus through the nuclear pore complex containing RanGap1. Chromatin immunoprecipitation cloning experiments demonstrated that nuclear TRAF6 associates with c-Myb within the 5′-end of the c-Myb promoter. Further analysis showed that nuclear TRAF6 is modified by small ubiquitin-related modifier-1, interacts with histone deacetylase 1, and represses c-Myb-mediated transactivation. Thus, TRAF6 negatively regulates c-Myb through a novel repressor function in the nuclei of both normal and malignant B-lymphocytes that could represent a novel control mechanism that maintains cell homeostasis and immune surveillance. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an adaptor/scaffold protein that mediates several important signaling pathways, including the tumor necrosis factor-R:NF-κB pathway, involved in immune surveillance, inflammation, etc. Because most studies of TRAF6 function have focused primarily on its role as an adaptor molecule in signaling pathways in the cytoplasm, the potential functions of TRAF6 in other cellular compartments has not been previously investigated. Here, we demonstrate that TRAF6 resides not only in the cellular cytoplasm but is also found in the nuclei of both normal and malignant B lymphocytes. TRAF6 does not possess a nuclear localization signal but enters the nucleus through the nuclear pore complex containing RanGap1. Chromatin immunoprecipitation cloning experiments demonstrated that nuclear TRAF6 associates with c-Myb within the 5′-end of the c-Myb promoter. Further analysis showed that nuclear TRAF6 is modified by small ubiquitin-related modifier-1, interacts with histone deacetylase 1, and represses c-Myb-mediated transactivation. Thus, TRAF6 negatively regulates c-Myb through a novel repressor function in the nuclei of both normal and malignant B-lymphocytes that could represent a novel control mechanism that maintains cell homeostasis and immune surveillance. The tumor necrosis factor (TNF) 2The abbreviations used are: TNFtumor necrosis factorTRAF6TNF receptor-associated factor 6E3ubiquitin-protein isopeptide ligaseIKK----SUMO-1small ubiquitin-related modifier-1HDAChistone deacetylasesiRNAsmall interference RNAChIPchromatin immunoprecipitationCMVcytomegalovirusGSTglutathione S-transferaseHAhemagglutininwtwild typePI3Kphosphatidylinositol 3-kinase. receptor family (e.g. CD40 and BAFF-R) plays a key role in normal as well as neoplastic B-cell growth and survival (1Fu L. Lin-Lee Y.C. Pham L.V. Tamayo A. Yoshimura L. Ford R.J. Blood. 2006; 107: 4540-4548Crossref PubMed Scopus (135) Google Scholar, 2Pham L.V. Tamayo A. Yoshimura L.C Lo P Ford R.J. Immunity. 2002; 16: 88-95Abstract Full Text Full Text PDF Scopus (107) Google Scholar). TNF receptor engagement results in the assembly of a cascade of signaling molecules composed of critical proteins, including adaptor molecules such as TNF receptor-associated factor 6 (TRAF6) that are recruited to the cell membrane and into lipid raft microdomains (3Bishop G.A. Nat. Rev. Immunol. 2004; 4: 775-786Crossref PubMed Scopus (126) Google Scholar). TRAF6 has been shown to act as an E3 ubiquitin ligase, allowing TRAF6 autoubiquitination, which further activates the IKK complex (4Deng L. Weng C. Spencer E. Yang L. Braun A. You J. Slaughter C. Pickart C. Chen Z.J. Cell. 2000; 103: 351-361Abstract Full Text Full Text PDF PubMed Scopus (1511) Google Scholar, 5Lamothe B. Webster W.K. Gopinathan A. Besse A. Campos A.D. Darnay B.G. Biochem. Biophys. Res. Commun. 2007; 359: 1044-1049Crossref PubMed Scopus (102) Google Scholar), leading to activation of key transcription factors such as NF-κB, NFAT, and AKT, all of which are critical for cell growth, survival, and osteoclast differentiation. Although ubiquitination normally targets a protein for degradation, TRAF6-mediated ubiquitination is independent of proteasomal degradation (5Lamothe B. Webster W.K. Gopinathan A. Besse A. Campos A.D. Darnay B.G. Biochem. Biophys. Res. Commun. 2007; 359: 1044-1049Crossref PubMed Scopus (102) Google Scholar, 6Chen Z.J. Nat. Cell. Biol. 2005; 7: 758-765Crossref PubMed Scopus (1022) Google Scholar, 7Lamothe B. Besse A. Campos A.D. Webster W.K. Wu H. Darnay B.G. J. Biol. Chem. 2007; 282: 4102-4112Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar), suggesting that the function of TRAF6 is broader than initially thought. tumor necrosis factor TNF receptor-associated factor 6 ubiquitin-protein isopeptide ligase ---- small ubiquitin-related modifier-1 histone deacetylase small interference RNA chromatin immunoprecipitation cytomegalovirus glutathione S-transferase hemagglutinin wild type phosphatidylinositol 3-kinase. TRAF6 is one of seven closely related TRAF proteins and was isolated by screening of an expressed sequence tag expression library utilizing CD40 as bait (8Ishida T. Mizushima S. Azuma S. Kobayashi N. Tojo T. Suzuki K. Aizawa S. Watanabe T. Mosialos G. Kieff E. Yamamoto T. Inoue J. J. Biol. Chem. 1996; 271: 28745-28748Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar). All TRAF protein sequences contain a C-terminal receptor-binding domain that mediates receptor binding. All of the TRAFs except for TRAF1 contain a variable number of zinc-finger motifs and a zinc ring domain (9Bradley J.R. Pober J.S. Oncogene. 2001; 20: 6482-6491Crossref PubMed Scopus (519) Google Scholar). The zinc-binding domains seem to function principally in mediating interactions with other proteins such as kinases and transcription factors that are involved in the propagation and regulation of signaling cascades. TRAF6 is unique among the TRAFs in showing the least homology to the prototypical TRAF domain sequence and interacting with both the TNF-receptor family members as well as the Toll-like receptor family for signaling (10Chung J.Y. Park Y.C. Ye H. Wu H. J. Cell Sci. 2002; 115: 679-688Crossref PubMed Google Scholar). TRAF6-deficient mice show defects in B-cell differentiation, lymph node organogenesis, osteoclastogenesis, and interleukin-1, lipopolysaccharide, and receptor activator of NF-κB signaling (11Choi Y. Adv. Exp. Med. Biol. 2005; 560: 77-82Crossref PubMed Scopus (18) Google Scholar). Because most studies of TRAF6 have focused primarily on its function as an adaptor molecule in cytoplasmic signaling pathways, the role of TRAF6 in other cellular compartments has not been investigated. Our recent studies have demonstrated that CD40, a TNF-receptor family member, is present in the nucleus of both normal and lymphoma B cells and also acts as a transcription factor (12Lin-Lee Y.C. Pham L.V. Tamayo A.T. Fu L. Zhou H.J. Yoshimura L.C. Decker G.L. Ford R.J. J. Biol. Chem. 2006; 281: 18878-18887Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 13Zhou H.J. Pham L.V. Tamayo A.T. Lin-Lee Y.C. Fu L. Yoshimura L.C. Ford R.J. Blood. 2007; 110: 2121-2127Crossref PubMed Scopus (39) Google Scholar). Recent studies by others revealed the presence of a membrane growth factor receptor (14Lin S.Y. Makino K. Xia W. Matin A. Wen Y. Kwong K.Y. Bourguignon L. Hung M.C. Nat. Cell. Biol. 2001; 3: 802-808Crossref PubMed Scopus (893) Google Scholar) and adaptor molecules (Daxx and TAB2) (15Lin D.Y. Huang Y.S. Jeng J.C. Kuo H.Y. Chang C.C. Chao T.T. Ho C.C. Chen Y.C. Lin T.P. Fang H.I. Hung C.C. Suen C.S. Hwang M.J. Chang K.S. Maul G.G. Shih H.M. Mol. Cell. 2006; 24: 341-354Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar, 16Sardi S.P. Murtie J. Koirala S. Patten B.A. Corfas G. Cell. 2006; 127: 185-197Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar) in the cell nucleus. These studies unveiled a new paradigm for cell signal transduction involving cell membrane and adaptor proteins trafficking into the cell nucleus. However, the functional roles of these proteins in the nucleus and how they enter the nucleus have yet to be fully defined. Recent studies have suggested that sumoylation, a post-translational protein modification step very similar to protein ubiquitination, involving covalent attachment of small ubiquitin-related modifier (SUMO) to lysine residues, is linked to nucleocytoplasmic protein transport and transcriptional gene repression (17Gill G. Curr. Opin. Genet. Dev. 2005; 15: 536-541Crossref PubMed Scopus (418) Google Scholar, 18Pichler A. Melchior F. Traffic. 2002; 3: 381-387Crossref PubMed Scopus (156) Google Scholar). Here, we demonstrate that TRAF6, a cytoplasmic adaptor protein, enters the nucleus through the nuclear pore complex involving RanGap-1, a Ran GTPase-activating enzyme. Further studies show that nuclear TRAF6 is modified by SUMO-1, interacts with histone deacetylase (HDAC) 1, and has the ability to repress c-Myb-mediated transactivation in B lymphocytes. Cells and Reagents–Human large B-cell lymphoma cell lines (MZ, McA, LR, MS, LP, and EJ) were established from diagnostic biopsy tissue or effusions from patients as described else-where (16Sardi S.P. Murtie J. Koirala S. Patten B.A. Corfas G. Cell. 2006; 127: 185-197Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar). The cells were cultured in RPMI medium (Invitrogen) containing 10% fetal calf serum (HyClone, Logan, UT). Normal human B lymphocytes were purified from donors' buffy coats by using the human B-cell enrichment mixture from StemCell Technologies (Vancouver, Canada). Antibodies and Small Interfering RNA Oligonucleotides–The following primary antibodies were used: polyclonal and monoclonal TRAF6, c-Myb, SUMO-1, RanGap-1, and HDAC1 (Santa Cruz Biotechnology, Santa Cruz, CA). Fluorescein isothiocyanate and Texas-Red-labeled secondary antibodies were purchased from Jackson ImmunoResearch Laboratories (West Grove, PA). Small-interfering RNA (siRNA) oligonucleotides for TRAF6 were purchased from Ambion (Austin, TX). Subcellular Fractionation of B Lymphoid Cells–Cellular fractionation procedures were performed as described previously (12Lin-Lee Y.C. Pham L.V. Tamayo A.T. Fu L. Zhou H.J. Yoshimura L.C. Decker G.L. Ford R.J. J. Biol. Chem. 2006; 281: 18878-18887Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). Chromatin Immunoprecipitation PCR and Cloning Assays–Chromatin immunoprecipitation (ChIP) cloning assays were performed using the ChIP assay kit and protocol provided by Millipore (Billerica, MA). Cells were cross-linked with 1% formaldehyde in culture medium for 10 min at 37 °C, washed with cold 1× phosphate-buffered saline, resuspended in SDS cell lysis buffer (provided with kit) for 10 min on ice, and sonicated three times at 10-s intervals. Samples were subjected to centrifugation for 10 min at 13,000 rpm at 4 °C, and the supernatants were diluted with ChIP dilution buffer. To reduce nonspecific background, samples were precleared with salmon sperm DNA and protein A-agarose (50% slurry) for 30 min at 4 °C with agitation. Primary antibodies were added to the samples that were incubated overnight at 4 °C. The slurry was added to each sample, which was then incubated for an additional hour. The protein A-antibody-DNA complexes were washed and eluted according to the manufacturer's protocol and then reverse cross-linked by heating at 65 °C for 4 h. DNA fragments were purified by proteinase K digestion, and DNA from and DNA were used for PCR with PCR from and for the c-Myb The PCR were as the was at °C for at °C for 30 and at °C for min for The PCR was on a cloning DNA fragments were in the containing and DNA at 37 °C for 30 min to DNA fragments were purified by proteinase K digestion, and The DNA fragments were by calf and into was subjected to DNA and analysis to the DNA sequence from the of the of were cross-linked to protein according to the manufacturer's Cell were precleared with protein for 30 min at 4 °C with overnight at 4 °C. The complexes were washed times with immunoprecipitation buffer and were eluted by in protein buffer and then for were with cold for and protein was by the cells with fetal calf serum in phosphate-buffered Cells were with the primary antibodies for at or overnight at 4 °C. three with phosphate-buffered saline, the were with the secondary with or for min and washed with phosphate-buffered were with The cells were using an were with a using the and expression in and have been previously described (5Lamothe B. Webster W.K. Gopinathan A. Besse A. Campos A.D. Darnay B.G. Biochem. Biophys. Res. Commun. 2007; 359: 1044-1049Crossref PubMed Scopus (102) Google Scholar). was performed using the kit from CA). All in were by DNA The c-Myb expression was a from of of PA). The was provided by A. of The expression was purchased from and lymphoma cells and B lymphocytes were according to the protocol from as described previously L.V. Tamayo A.T. Yoshimura L.C. Lo Ford R.J. J. Immunol. PubMed Scopus Google Scholar). and assays were performed according to the manufacturer's assay was at least three times in experiments with similar were to using the expression assays were performed using proteins and the according to the protocol from assays were performed by lymphoma cells with and expression as cell nuclear were subjected to immunoprecipitation and analysis as described of TRAF6 in B the nuclear role of CD40 in lymphoma B we the presence of TRAF6 protein in the nuclei of cells from B-cell lymphoma cell lines by nuclear cell fractionation and of the TRAF protein on the other was primarily in the cytoplasmic and was used as a and were also found in the but at in to TRAF6 not TRAF6 is also present in the nuclei of both and and B lymphocytes for on B To further the localization of TRAF6 in lymphoma B we used as well as fractionation shown in analysis demonstrated that TRAF6 protein was expressed not only in the membrane and cellular cytoplasm but also in the nucleus of lymphoma B TRAF6 protein expression was not the but was expressed in nuclear protein complexes in the nuclear demonstrated using from analysis was primarily in the cytoplasm Cell fractionation studies in lymphoma cell lines that TRAF6 was also present in the suggesting that TRAF6 with chromatin TRAF6 in B has been shown to function as an E3 ubiquitin ligase and is of To TRAF6 was in lymphoma B analysis was performed using polyclonal with cytoplasmic and nuclear purified from a lymphoma cell shown in TRAF6 is in the cytoplasmic but not in the nuclear suggesting that TRAF6 have a role other than ubiquitination in the nucleus. ChIP cloning analysis using polyclonal revealed a of one of which a to the 5′-end of the c-Myb promoter. ChIP analysis by reverse the of TRAF6 with the c-Myb c-Myb is to to its in the as TRAF6 The other DNA that not However, the of the sequences DNA that is in the of both and not The of TRAF6 with or that TRAF6 have a role in gene transcriptional To TRAF6 has transcriptional activation assays were performed by TRAF6 to the domain and then the into lymphoma the protein showed transactivation suggesting that the TRAF6 protein act as a transcriptional in the nuclei of lymphoma B of TRAF6 with c-Myb in of DNA of the c-Myb which was with TRAF6 using ChIP cloning a c-Myb The other were also for transcription factor that of the sequences as containing at least one c-Myb not These that TRAF6 interacts with through to the c-Myb Immunoprecipitation assays showed that TRAF6 interacts with c-Myb that was by analysis Because the assays demonstrated that TRAF6 has transcriptional repression we TRAF6 could be involved in c-Myb-mediated transcriptional B-cell lymphoma cells were with a in with a c-Myb expression and with of expression of TRAF6 c-Myb-mediated transcriptional in a To further the TRAF6-mediated transcriptional repression of c-Myb, normal B-lymphocytes were with a TRAF6 expression with the by CD40 and Normal B-cell activation by CD40 and c-Myb transcriptional TRAF6 also c-Myb transcriptional by CD40 and in normal B-lymphocytes further that TRAF6 negatively regulates c-Myb-mediated TRAF6 represses c-Myb transcriptional To we TRAF6 protein expression using an RNA interference of a TRAF6 into lymphoma B cells in a of cellular TRAF6 protein the of protein these TRAF6 c-Myb-mediated transactivation further the of nuclear TRAF6 on c-Myb transcriptional TRAF6 by in B that sumoylation, a protein modification that of the small protein is with gene transcriptional the proteins, only a nuclear localization signal that functions by the protein into the nucleus. assays demonstrated that TRAF6 with in the cytoplasm as well as in the nucleus The nuclear TRAF6 and to in nuclear complexes by for Immunoprecipitation with TRAF6 to demonstrated with monoclonal three protein of and in the nuclear but were not present in cytoplasmic or Because the TRAF6 protein is the protein could represent TRAF6, and the and could represent proteins that with Further analysis by and that the is a Ran GTPase-activating with SUMO-1, and protein with TRAF6 at the nuclear membrane suggesting that TRAF6 enters the nucleus through the nuclear pore The protein has not as yet been To demonstrate that TRAF6 is modified by SUMO-1, we performed in assays by proteins with containing protein with in the that TRAF6 and but not in the or or in the with These results that the is in a TRAF6 To TRAF6 proteins were from purified cytoplasmic of a lymphoma cell and incubated with as in were by using an or was in the with TRAF6 and but was not present in the or with TRAF6 could be by the domain of further that TRAF6 is modified by to TRAF6 is modified by in and to the of TRAF6 involved in on B. 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