Key points are not available for this paper at this time.
BAFF receptor (BAFFR) is a member of the TNF receptor (TNFR) superfamily that regulates the survival and maturation of B cells. BAFFR exerts its signaling function by inducing activation of NF-κB, although the underlying mechanism has not been well defined. By using a chimeric BAFFR, we show that BAFFR preferentially induces the noncanonical NF-κB signaling pathway. This specific function of BAFFR is mediated by a sequence motif, PVPAT, which is homologous to the TRAF-binding site (PVQET) present in CD40, a TNFR known to induce both the canonical and noncanonical NF-κB pathways. Mutation of this putative TRAF-binding motif within BAFFR abolishes its interaction with TRAF3 as well as its ability to induce noncanonical NF-κB. Interestingly, modification of the PVPAT sequence to the typical TRAF-binding sequence, PVQET, is sufficient to render the BAFFR capable of inducing strong canonical NF-κB signaling. Further, this functional acquisition of the modified BAFFR is associated with its stronger and more rapid association with TRAF3. These findings suggest that the PVPAT sequence of BAFFR not only functions as a key signaling motif of BAFFR but also determines its signaling specificity in the induction of the noncanonical NF-κB pathway. BAFF receptor (BAFFR) is a member of the TNF receptor (TNFR) superfamily that regulates the survival and maturation of B cells. BAFFR exerts its signaling function by inducing activation of NF-κB, although the underlying mechanism has not been well defined. By using a chimeric BAFFR, we show that BAFFR preferentially induces the noncanonical NF-κB signaling pathway. This specific function of BAFFR is mediated by a sequence motif, PVPAT, which is homologous to the TRAF-binding site (PVQET) present in CD40, a TNFR known to induce both the canonical and noncanonical NF-κB pathways. Mutation of this putative TRAF-binding motif within BAFFR abolishes its interaction with TRAF3 as well as its ability to induce noncanonical NF-κB. Interestingly, modification of the PVPAT sequence to the typical TRAF-binding sequence, PVQET, is sufficient to render the BAFFR capable of inducing strong canonical NF-κB signaling. Further, this functional acquisition of the modified BAFFR is associated with its stronger and more rapid association with TRAF3. These findings suggest that the PVPAT sequence of BAFFR not only functions as a key signaling motif of BAFFR but also determines its signaling specificity in the induction of the noncanonical NF-κB pathway. B cell-activating factor belonging to the TNF 1The abbreviations used are: TNF, tumor necrosis factor; TNFR, TNF receptor; BAFF, B cell-activating factor belonging to the TNF family; BAFFR, BAFF receptor; TACI, transmembrane activator and calcium modulator and cyclophilin ligand interactor; BCMA, B cell maturation antigen; IKK, IκB kinase; LTβR, lymphotoxin β receptor; TRAF, TNF receptor-associated factor; FACS, fluorescence-activated cell sorting; IB, immunoblotting; EMSA, electrophoresis mobility shift assay; hCD40, human CD40; RPA, RNase protection assay; HRP, horseradish peroxidase; HA, hemagglutinin.1The abbreviations used are: TNF, tumor necrosis factor; TNFR, TNF receptor; BAFF, B cell-activating factor belonging to the TNF family; BAFFR, BAFF receptor; TACI, transmembrane activator and calcium modulator and cyclophilin ligand interactor; BCMA, B cell maturation antigen; IKK, IκB kinase; LTβR, lymphotoxin β receptor; TRAF, TNF receptor-associated factor; FACS, fluorescence-activated cell sorting; IB, immunoblotting; EMSA, electrophoresis mobility shift assay; hCD40, human CD40; RPA, RNase protection assay; HRP, horseradish peroxidase; HA, hemagglutinin. family (BAFF) is a critical factor that regulates the survival and maturation of peripheral B cells (1Mackay F. Tangye S.G. Curr. Opin. Pharmacol. 2004; 4: 347-354Crossref PubMed Scopus (107) Google Scholar). BAFF interacts with three receptors of the TNF receptor (TNFR) superfamily: transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI), B cell maturation antigen (BCMA), and BAFF receptor (BAFFR). Genetic evidence suggests that BAFFR is primarily responsible for mediating the role of BAFF in B-cell survival and maturation (2Thompson J.S. Bixler S.A. Qian F. Vora K. Scott M.L. Cachero T.G. Hession C. Schneider P. Sizing I.D. Mullen C. Strauch K. Zafari M. Benjamin C.D. Tschopp J. Browning J.L. Ambrose C. Science. 2001; 293: 2108-2111Crossref PubMed Scopus (761) Google Scholar, 3Yan M. Brady J.R. Chan B. Lee W.P. Hsu B. Harless S. Cancro M. Grewal I.S. Dixit V.M. Curr. Biol. 2001; 11: 1547-1552Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar, 4Sasaki Y. Casola S. Kutok J.L. Rajewsky K. Schmidt-Supprian M. J. Immunol. 2004; 173: 2245-2252Crossref PubMed Scopus (289) Google Scholar, 5Shulga-Morskaya S. Dobles M. Walsh M.E. Ng L.G. MacKay F. Rao S.P. Kalled S.L. Scott M.L. J. Immunol. 2004; 173: 2331-2341Crossref PubMed Scopus (199) Google Scholar). It is generally believed that the BAFF/BAFFR system mediates B-cell survival by promoting the expression of anti-apoptosis genes belonging to the Bcl-2 family, such as A1 (also named Bfl-1) and Bcl-XL (6Patke A. Mecklenbrauker I. Tarakhovsky A. Curr. Opin. Immunol. 2004; 16: 251-255Crossref PubMed Scopus (52) Google Scholar). The BAFFR signal appears to function in cooperation with other signals, especially those elicited by the B-cell receptor (6Patke A. Mecklenbrauker I. Tarakhovsky A. Curr. Opin. Immunol. 2004; 16: 251-255Crossref PubMed Scopus (52) Google Scholar), because recombinant BAFF is insufficient to trigger significant expression of the anti-apoptosis genes in cell culture (7Trescol-Biemont M.C. Verschelde C. Cottalorda A. Bonnefoy-Berard N. Biochimie. (Paris). 2004; 86: 287-294Crossref PubMed Scopus (21) Google Scholar, 8Zarnegar B. He J.Q. Oganesyan G. Hoffmann A. Baltimore D. Cheng G. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 8108-8113Crossref PubMed Scopus (101) Google Scholar). A major signaling event induced by BAFF is activation of NF-κB, a family of inducible transcription factors that play pivotal roles in regulating diverse aspects of immune function (9Ghosh S. May M.J. Kopp E.B. Annu. Rev. Immunol. 1998; 16: 225-260Crossref PubMed Scopus (4550) Google Scholar, 10Karin M. Delhase M. Semin. Immunol. 2000; 12: 85-98Crossref PubMed Scopus (834) Google Scholar, 11Silverman N. Maniatis T. Genes Dev. 2001; 15: 2321-2342Crossref PubMed Scopus (765) Google Scholar). The NF-κB family is composed of five members: RelA, RelB, c-Rel, NF-κB1, and NF-κB2, which function as various dimeric complexes that transactivate specific target genes via binding to the κB enhancer (12Siebenlist U. Franzoso G. Brown K. Annu. Rev. Cell Biol. 1994; 10: 405-455Crossref PubMed Scopus (2003) Google Scholar). The function of NF-κB is normally suppressed by their physical association with inhibitory proteins, including IκBα and homologs as well as the NF-κB1 and NF-κB2 precursor proteins, p105 and p100 (13Baldwin Jr., A.S. Annu. Rev. Immunol. 1996; 14: 649-683Crossref PubMed Scopus (5515) Google Scholar). Activation of NF-κB by most cellular inducers involves phosphorylation and subsequent degradation of IκBα and the concomitant nuclear translocation of p50/RelA and p50/c-Rel NF-κB complexes (14Karin M. Ben-Neriah Y. Annu. Rev. Immunol. 2000; 18: 621-663Crossref PubMed Scopus (4024) Google Scholar). This so-called canonical pathway of NF-κB activation is mediated by a multisubunit IκB kinase (IKK) composed of two catalytic subunits, IKKα and IKKβ, and a regulatory subunit, IKKγ (14Karin M. Ben-Neriah Y. Annu. Rev. Immunol. 2000; 18: 621-663Crossref PubMed Scopus (4024) Google Scholar). Recently, another mechanism of NF-κB activation has been identified, which is based on the inducible processing of the NF-κB2 precursor protein p100 (15Xiao G. Harhaj E.W. Sun S.C. Mol. Cell. 2001; 7: 401-409Abstract Full Text Full Text PDF PubMed Scopus (665) Google Scholar), an IκB-like molecule specifically inhibiting the nuclear translocation of RelB (16Solan N.J. Miyoshi H. Carmona E.M. Bren G.D. Paya C.V. J. Biol. Chem. 2002; 277: 1405-1418Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). This mechanism, known as the noncanonical NF-κB pathway, is required for generation of p52 as well as the nuclear translocation of RelB-containing NF-κB complexes (17Pomerantz J.L. Baltimore D. Mol. Cell. 2002; 10: 693-695Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar). Interestingly, activation of the noncanonical NF-κB pathway is specifically mediated by a subset of TNFR family members, including BAFFR, CD40, lymphotoxin β receptor, and receptor activator of NF-κB (18Claudio E. Brown K. Park S. Wang H. Siebenlist U. Nat. Immunol. 2002; 3: 958-965Crossref PubMed Scopus (570) Google Scholar, 19Coope H.J. Atkinson P.G. Huhse B. Belich M. Janzen J. Holman M.J. Klaus G.G. Johnston L.H. Ley S.C. EMBO J. 2002; 15: 5375-5385Crossref Scopus (363) Google Scholar, 20Dejardin E. Droin N.M. Delhase M. Haas E. Cao Y. Makris C. Li Z.W. Karin M. Ware C.F. Green D.R. Immunity. 2002; 17: 525-535Abstract Full Text Full Text PDF PubMed Scopus (767) Google Scholar, 21Kayagaki N. Yan M. Seshasayee D. Wang H. Lee W. French D.M. Grewal I.S. Cochran A.G. Gordon N.C. Yin J. Starovasnik M.A. Dixit V.M. Immunity. 2002; 17: 515-524Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar, 22Novack D.V. Yin L. Hagen-Stapleton A. Schreiber R.D. Goeddel D.V. Ross F.P. Teitelbaum S.L. J. Exp. Med. 2003; 198: 771-781Crossref PubMed Scopus (224) Google Scholar). Like BAFFR, CD40 plays an important role in regulating the function of B cells, although these two receptors regulate different aspects of B-cell function. Whereas BAFFR regulates the maturation of B cells, CD40 is particularly important for the survival and differentiation of antigen-activated B cells in the germinal centers (23van Kooten C. Banchereau J. J. Leukoc. Biol. 2000; 67: 2-17Crossref PubMed Scopus (1160) Google Scholar). Although the signaling mechanism of BAFFR remains poorly understood, the signaling function of CD40 has been extensively studied. The cytoplasmic domain of CD40 contains specific motifs for binding to members of the TNFR-associated factors (TRAF) (23van Kooten C. Banchereau J. J. Leukoc. Biol. 2000; 67: 2-17Crossref PubMed Scopus (1160) Google Scholar). One such motif, PVQET, predominantly interacts with two TRAF members, TRAF2 and TRAF3 (23van Kooten C. Banchereau J. J. Leukoc. Biol. 2000; 67: 2-17Crossref PubMed Scopus (1160) Google Scholar). This TRAF-binding motif, with the consensus sequence of PXQXT(S), has also been found in several other TNFR family members (24Bradley J.R. Pober J.S. Oncogene. 2001; 20: 6482-6491Crossref PubMed Scopus (507) Google Scholar). CD40 is able to induce the activation of both noncanonical and canonical NF-κB signaling pathways (8Zarnegar B. He J.Q. Oganesyan G. Hoffmann A. Baltimore D. Cheng G. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 8108-8113Crossref PubMed Scopus (101) Google Scholar, 19Coope H.J. Atkinson P.G. Huhse B. Belich M. Janzen J. Holman M.J. Klaus G.G. Johnston L.H. Ley S.C. EMBO J. 2002; 15: 5375-5385Crossref Scopus (363) Google Scholar). Further, ligation of CD40 is sufficient for triggering the expression of various target genes, including those encoding the apoptosis inhibitors Bfl-1/A1 and Bcl-XL (25Lee H.H. Dadgostar H. Cheng Q. Shu J. Cheng G. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 9136-9141Crossref PubMed Scopus (482) Google Scholar). Unlike CD40, BAFFR does not contain a conserved TRAF-binding motif. The signaling determinant of BAFFR has not been well defined, although truncation at its C-terminal region abolishes its signaling function (2Thompson J.S. Bixler S.A. Qian F. Vora K. Scott M.L. Cachero T.G. Hession C. Schneider P. Sizing I.D. Mullen C. Strauch K. Zafari M. Benjamin C.D. Tschopp J. Browning J.L. Ambrose C. Science. 2001; 293: 2108-2111Crossref PubMed Scopus (761) Google Scholar, 3Yan M. Brady J.R. Chan B. Lee W.P. Hsu B. Harless S. Cancro M. Grewal I.S. Dixit V.M. Curr. Biol. 2001; 11: 1547-1552Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar, 21Kayagaki N. Yan M. Seshasayee D. Wang H. Lee W. French D.M. Grewal I.S. Cochran A.G. Gordon N.C. Yin J. Starovasnik M.A. Dixit V.M. Immunity. 2002; 17: 515-524Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar). The precise role of BAFFR in mediating different pathways of NF-κB activation also remains unclear. Whereas BAFFR clearly mediates the induction of the noncanonical NF-κB signaling pathway (18Claudio E. Brown K. Park S. Wang H. Siebenlist U. Nat. Immunol. 2002; 3: 958-965Crossref PubMed Scopus (570) Google Scholar, 21Kayagaki N. Yan M. Seshasayee D. Wang H. Lee W. French D.M. Grewal I.S. Cochran A.G. Gordon N.C. Yin J. Starovasnik M.A. Dixit V.M. Immunity. 2002; 17: 515-524Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar), its role in activating the canonical pathway remains ambiguous (8Zarnegar B. He J.Q. Oganesyan G. Hoffmann A. Baltimore D. Cheng G. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 8108-8113Crossref PubMed Scopus (101) Google Scholar, 26Hatada E.N. Do R.K. Orlofsky A. Liou H.C. Prystowsky M. MacLennan I.C. Caamano J. Chen-Kiang S. J. Immunol. 2003; 171: 761-768Crossref PubMed Scopus (114) Google Scholar). One complexity that may contribute to the discrepancy of the prior studies is the involvement of different BAFF-responding receptors: TACI, BCMA, and BAFFR (27Mackay F. Schneider P. Rennert P. Browning J. Annu. Rev. Immunol. 2003; 21: 231-264Crossref PubMed Scopus (764) Google Scholar). In the present we the specific signaling function of BAFFR using a chimeric receptor the ligand binding domain of CD40 and the signaling domain of show that the BAFFR predominantly the activation of noncanonical NF-κB. we a signaling motif of BAFFR that is critical for its signaling function in NF-κB This motif is homologous to the TRAF-binding site of CD40, although does not contain the conserved of the typical TRAF-binding motif. of the conserved with abolishes the function of BAFFR in the induction of p100 Interestingly, of the BAFFR signaling motif to the typical TRAF-binding sequence the BAFFR in activation of both the noncanonical and canonical NF-κB pathways. These findings suggest that the TRAF-binding sequence of BAFFR not only functions as a key signaling motif but also determines the signaling of BAFFR in mediating noncanonical NF-κB the and transmembrane of human CD40 and the cytoplasmic domain of BAFFR The by using human and B cell and the by M. E. Haas M. J. 1996; PubMed Google the and using as to the in the cytoplasmic domain of G. M. Harhaj E.W. Sun S.C. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus (363) Google Scholar). The for and at the of of the used in this at the of of and for TRAF3 and RelB and Science. CD40 and a The The Cell and B cell in this T. J. Immunol. Google and its with S.A. J. Immunol. 2002; PubMed Scopus (52) Google by A. The and cells by the cells with the encoding and of the as I. M.E. G. Sun S.C. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). cells used in the to of these B-cell in with and The cell in with the the of of cells using I. M.E. G. Sun S.C. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), the cells with Cell cells in of in The cells with and to using a at the of Cell RNase cellular and cells using the RNase protection using the and to the and cell in G. M.E. A. Harhaj E.W. M. Sun S.C. EMBO J. 2001; 20: PubMed Scopus Google Scholar), and nuclear as Science. PubMed Scopus Google Scholar). The in and to using the and M. L. G. Harhaj E.W. E. Karin M. Sun J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). to using a κB Science. PubMed Scopus Google Scholar). to The to J. Immunol. 2002; PubMed Scopus Google Scholar). cells and in of and for the with The cells with and in of a and of a The protein in at for with of protein to the immune the with for three the TRAF3 the with and by using BAFFR the NF-κB the signaling function of BAFFR, we a chimeric receptor the cytoplasmic domain of BAFFR and the domain of human CD40 this the signaling of BAFFR with an the of and the Further, this chimeric receptor of the signaling functions of BAFFR and CD40 using the By we the in a B cell T. J. Immunol. Google Scholar), which has been used as a for the signaling function of both CD40 J. Immunol. 2002; PubMed Scopus Google Scholar, J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, E. M. J. Immunol. 2002; PubMed Scopus Google and BAFFR G. M. Harhaj E.W. Sun S.C. J. Biol. 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Chem. 2004; Full Text Full Text PDF PubMed Scopus (363) Google Scholar), we the BAFFR also induces TRAF3 TRAF3 concomitant with the induction of p100 processing by both and the CD40 The of TRAF3 not to its translocation to the not and at of cell the we BAFFR the canonical NF-κB signaling pathway by degradation of with the ability of CD40 to canonical NF-κB, of cells in degradation of IκBα In of the cells only to a of IκBα This not to the expression of Further, because the p100 processing more induced by the is that the of in inducing IκBα degradation to its signaling CD40, BAFFR is a TNFR member that preferentially the noncanonical NF-κB signaling pathway. TRAF-binding for BAFFR signaling function of TRAF A specific TRAF-binding motif has been in a of TNFR members He J.Q. Cheng G. Rev. 2003; 14: PubMed Scopus Google Scholar), with those in CD40 the most extensively 1998; PubMed Scopus Google Scholar). the mechanism mediating the signaling function of BAFFR, we the of the cytoplasmic of BAFFR and Interestingly, although BAFFR a typical TRAF-binding motif, a sequence that significant in both and sequence, with the TRAF-binding motif of CD40 and the role of this sequence in BAFFR we to the conserved within the with In we also the BAFFR motif to the typical TRAF-binding sequence, PVQET, of CD40 a expression the and of the PVPAT to the ability to induce p100 processing the other the in inducing p100 processing The but not also the induction of TRAF3 degradation A using that the TRAF3 degradation by BAFFR and receptor but this not in cells the a of p100 processing is nuclear translocation of RelB and p52 NF-κB we the expression of these two NF-κB members in the of the different cells. of the cells by both RelB and p52 in the two In with the of p100 the of the to the inducible nuclear expression of RelB and p52 the in this signaling function these the PVPAT sequence as a key signaling motif of BAFFR that mediates the induction of p100 processing and nuclear expression of the noncanonical NF-κB The PVPAT the of important BAFFR signaling is its signaling specificity is in and BAFFR preferentially the noncanonical NF-κB signaling pathway, CD40 both the canonical and noncanonical NF-κB pathways. One we that the signaling function of BAFFR to its of an TRAF-binding motif. this we the of within the cytoplasmic domain of BAFFR on its ability to induce IκBα of the only to a of IκBα degradation which not in the of the receptor of the PVPAT sequence to the BAFFR capable of degradation of IκBα a in the putative TRAF-binding site of BAFFR is sufficient to a receptor capable of the canonical pathway of NF-κB. One major the canonical and noncanonical NF-κB pathways in their signaling Whereas the canonical pathway is rapid and the noncanonical pathway is and to the and of NF-κB activation by the and of the of cell the BAFFR only mediated a activation of NF-κB and but the of BAFFR a stronger activation of NF-κB the and This with the induction of IκBα degradation by the In to the NF-κB in the NF-κB activation mediated by the and of BAFFR and Further, the of BAFFR in activation of both the and of the PVPAT motif of BAFFR specifically mediates the activation of NF-κB, which in is associated with the processing of p100 and nuclear translocation of and the signaling specificity of BAFFR, we the expression of studies suggest that the BAFFR signal is insufficient for triggering significant induction of genes, such as Bfl-1/A1 (7Trescol-Biemont M.C. Verschelde C. Cottalorda A. Bonnefoy-Berard N. Biochimie. (Paris). 2004; 86: 287-294Crossref PubMed Scopus (21) Google Scholar). In the Bfl-1/A1 by the CD40 signal (25Lee H.H. Dadgostar H. Cheng Q. Shu J. Cheng G. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 9136-9141Crossref PubMed Scopus (482) Google Scholar, A. A. M. C. D. J. 2004; PubMed Scopus Google Scholar). the of this in cells the chimeric BAFFR with the prior of the BAFFR not induce the expression of Bfl-1/A1 Interestingly, of the BAFFR to induction of Bfl-1/A1 these suggest that the TRAF-binding motif of BAFFR not only as a key signaling motif but also regulates its signaling The PVPAT of TRAF3 to prior that BAFFR specifically interacts with TRAF3 Shu J. Immunol. 2002; PubMed Scopus Google Scholar). the role of the PVPAT motif in TRAF we the of TRAF3 to the receptor in cells with In with the we found that TRAF3 to the BAFFR ligation by although significant association not this physical interaction the PVPAT motif, because the the to TRAF3 Interestingly, the the with TRAF3 more and more the BAFFR This of the BAFFR of the CD40 which and with TRAF3 in to the These the functional studies the PVPAT to sufficient to render the modified BAFFR capable of binding to These studies using cells. with a the BAFFR not with TRAF2 the the in this physical interaction Interestingly, the which the motif, a significant these suggest that the TRAF-binding motif of BAFFR specifically interacts with TRAF3 but not with which to the signaling specificity of Further, of the TRAF-binding motif to a conserved is sufficient to the specificity of BAFFR in TRAF binding and NF-κB signaling. The of this an the signaling mechanism of a signaling motif, PVPAT, within the cytoplasmic domain of BAFFR that significant sequence with the TRAF-binding motif, PVQET, of the BAFFR motif does not the consensus sequence of the TRAF-binding sequence present in several TNFR superfamily that this TRAF-binding motif is responsible for the signaling of BAFFR that preferentially the noncanonical NF-κB pathway. several of evidence that this of the conserved within the PVPAT motif abolishes the ability of BAFFR to induce p100 processing and nuclear translocation of RelB and p52 key in noncanonical NF-κB signaling (17Pomerantz J.L. Baltimore D. Mol. Cell. 2002; 10: 693-695Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar). a that the PVPAT sequence to the typical TRAF-binding sequence (PVQET) the modified BAFFR in activating the canonical NF-κB pathway the PVPAT motif is for the association of BAFFR with and the the of BAFFR we also that PVPAT to has on p100 processing the activation of NF-κB but this the NF-κB activation known to associated with canonical NF-κB signaling. the PVPAT to sequence the modified BAFFR to with which may contribute to the in the canonical NF-κB signaling. that TRAF3 functions as a of p100 processing induced by CD40 and BAFFR G. M. Harhaj E.W. Sun S.C. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus (363) Google Scholar). suggests that of TRAF3 to BAFFR is critical for induction of p100 The of BAFFR, which is in also to induce p100 It is the TRAF3 to BAFFR to signal to p100 One is that the receptor as a trigger for the degradation of which appears to an important in the noncanonical NF-κB signaling pathway G. M. Harhaj E.W. Sun S.C. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus (363) Google Scholar). In of this the BAFFR to induce TRAF3 degradation also remains that the receptor of TRAF3 plays an role in the of the noncanonical NF-κB signaling. of this B cells TRAF3. TRAF2 and TRAF3 generally to to the sequence present in the cytoplasmic of TNFR family members (23van Kooten C. Banchereau J. J. Leukoc. Biol. 2000; 67: 2-17Crossref PubMed Scopus (1160) Google Scholar). using the cytoplasmic domain of CD40 that TRAF2 and TRAF3 in target sequence 1998; PubMed Scopus Google Scholar). suggest that the TRAF-binding sequence within BAFFR binding to TRAF3 but does not with This may in contribute to the signaling specificity of BAFFR in the induction of noncanonical NF-κB In of this of the TRAF-binding motif to a conserved TRAF-binding motif the modified BAFFR to with both TRAF3 and TRAF2 and to target both the noncanonical and canonical NF-κB signaling pathways. G. for and cells and I. M. for the also and the of of for in and
Morrison et al. (Wed,) studied this question.