Stoichiometry of Heteromeric BAFF and APRIL Cytokines Dictates Their Receptor Binding and Signaling Properties
The closely related TNF family ligands B cell activation factor (BAFF) and aproliferation-inducing ligand (APRIL) serve in the generation and maintenance of mature B-lymphocytes. Both BAFF and APRIL assemble as homotrimers that bind and activate several receptors that they partially share. However,...
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| Veröffentlicht in: | The Journal of biological chemistry 2015-06, Vol.290 (26), p.16330-16342 |
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| creator | Schuepbach-Mallepell, Sonia Das, Dolon Willen, Laure Vigolo, Michele Tardivel, Aubry Lebon, Luc Kowalczyk-Quintas, Christine Nys, Josquin Smulski, Cristian Zheng, Timothy S. Maskos, Klaus Lammens, Alfred Jiang, Xuliang Hess, Henry Tan, Seng-Lai Schneider, Pascal |
| description | The closely related TNF family ligands B cell activation factor (BAFF) and aproliferation-inducing ligand (APRIL) serve in the generation and maintenance of mature B-lymphocytes. Both BAFF and APRIL assemble as homotrimers that bind and activate several receptors that they partially share. However, heteromers of BAFF and APRIL that occur in patients with autoimmune diseases are incompletely characterized. The N and C termini of adjacent BAFF or APRIL monomers are spatially close and can be linked to create single-chain homo- or hetero-ligands of defined stoichiometry. Similar to APRIL, heteromers consisting of one BAFF and two APRILs (BAA) bind to the receptors B cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) but not to the BAFF receptor (BAFFR). Heteromers consisting of one APRIL and two BAFF (ABB) bind to TACI and BCMA and weakly to BAFFR in accordance with the analysis of the receptor interaction sites in the crystallographic structure of ABB. Receptor binding correlated with activity in reporter cell line assays specific for BAFFR, TACI, or BCMA. Single-chain BAFF (BBB) and to a lesser extent single-chain ABB, but not APRIL or single-chain BAA, rescued BAFFR-dependent B cell maturation in BAFF-deficient mice. In conclusion, BAFF-APRIL heteromers of different stoichiometries have distinct receptor-binding properties and activities. Based on the observation that heteromers are less active than BAFF, we speculate that their physiological role might be to down-regulate BAFF activity.
Background: The B cell survival factors B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) can heteromerize.
Results: BAFF-APRIL2 and APRIL-BAFF2 heteromers have distinct receptor-binding specificities and activities.
Conclusion: BAFF-APRIL2 resembles APRIL, and APRIL-BAFF2 resembles BAFF but poorly activates the BAFF receptor.
Significance: Heteromers should be taken into account when evaluating the physiology or pharmacological inhibition of BAFF and APRIL. |
| doi_str_mv | 10.1074/jbc.M115.661405 |
| format | Article |
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Background: The B cell survival factors B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) can heteromerize.
Results: BAFF-APRIL2 and APRIL-BAFF2 heteromers have distinct receptor-binding specificities and activities.
Conclusion: BAFF-APRIL2 resembles APRIL, and APRIL-BAFF2 resembles BAFF but poorly activates the BAFF receptor.
Significance: Heteromers should be taken into account when evaluating the physiology or pharmacological inhibition of BAFF and APRIL.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M115.661405</identifier><identifier>PMID: 25953898</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; APRIL ; B-Cell Activating Factor - chemistry ; B-Cell Activating Factor - genetics ; B-Cell Activating Factor - metabolism ; B-Cell Activation Factor Receptor - genetics ; B-Cell Activation Factor Receptor - metabolism ; B-Cell Maturation Antigen - genetics ; B-Cell Maturation Antigen - metabolism ; BAFF ; cytokine ; Dimerization ; heteromers ; Humans ; Immunology ; Ligands ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; Protein Binding ; protein engineering ; receptor ; Signal Transduction ; signaling ; Transmembrane Activator and CAML Interactor Protein - genetics ; Transmembrane Activator and CAML Interactor Protein - metabolism ; Tumor Necrosis Factor Ligand Superfamily Member 13 - chemistry ; Tumor Necrosis Factor Ligand Superfamily Member 13 - genetics ; Tumor Necrosis Factor Ligand Superfamily Member 13 - metabolism</subject><ispartof>The Journal of biological chemistry, 2015-06, Vol.290 (26), p.16330-16342</ispartof><rights>2015 © 2015 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2015 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><rights>2015 by The American Society for Biochemistry and Molecular Biology, Inc. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-7f7b025ae5ef904b31f72cee056badcb05f0767da0957f53ba25eccfc7d057043</citedby><cites>FETCH-LOGICAL-c443t-7f7b025ae5ef904b31f72cee056badcb05f0767da0957f53ba25eccfc7d057043</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481231/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481231/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25953898$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schuepbach-Mallepell, Sonia</creatorcontrib><creatorcontrib>Das, Dolon</creatorcontrib><creatorcontrib>Willen, Laure</creatorcontrib><creatorcontrib>Vigolo, Michele</creatorcontrib><creatorcontrib>Tardivel, Aubry</creatorcontrib><creatorcontrib>Lebon, Luc</creatorcontrib><creatorcontrib>Kowalczyk-Quintas, Christine</creatorcontrib><creatorcontrib>Nys, Josquin</creatorcontrib><creatorcontrib>Smulski, Cristian</creatorcontrib><creatorcontrib>Zheng, Timothy S.</creatorcontrib><creatorcontrib>Maskos, Klaus</creatorcontrib><creatorcontrib>Lammens, Alfred</creatorcontrib><creatorcontrib>Jiang, Xuliang</creatorcontrib><creatorcontrib>Hess, Henry</creatorcontrib><creatorcontrib>Tan, Seng-Lai</creatorcontrib><creatorcontrib>Schneider, Pascal</creatorcontrib><title>Stoichiometry of Heteromeric BAFF and APRIL Cytokines Dictates Their Receptor Binding and Signaling Properties</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>The closely related TNF family ligands B cell activation factor (BAFF) and aproliferation-inducing ligand (APRIL) serve in the generation and maintenance of mature B-lymphocytes. Both BAFF and APRIL assemble as homotrimers that bind and activate several receptors that they partially share. However, heteromers of BAFF and APRIL that occur in patients with autoimmune diseases are incompletely characterized. The N and C termini of adjacent BAFF or APRIL monomers are spatially close and can be linked to create single-chain homo- or hetero-ligands of defined stoichiometry. Similar to APRIL, heteromers consisting of one BAFF and two APRILs (BAA) bind to the receptors B cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) but not to the BAFF receptor (BAFFR). Heteromers consisting of one APRIL and two BAFF (ABB) bind to TACI and BCMA and weakly to BAFFR in accordance with the analysis of the receptor interaction sites in the crystallographic structure of ABB. Receptor binding correlated with activity in reporter cell line assays specific for BAFFR, TACI, or BCMA. Single-chain BAFF (BBB) and to a lesser extent single-chain ABB, but not APRIL or single-chain BAA, rescued BAFFR-dependent B cell maturation in BAFF-deficient mice. In conclusion, BAFF-APRIL heteromers of different stoichiometries have distinct receptor-binding properties and activities. Based on the observation that heteromers are less active than BAFF, we speculate that their physiological role might be to down-regulate BAFF activity.
Background: The B cell survival factors B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) can heteromerize.
Results: BAFF-APRIL2 and APRIL-BAFF2 heteromers have distinct receptor-binding specificities and activities.
Conclusion: BAFF-APRIL2 resembles APRIL, and APRIL-BAFF2 resembles BAFF but poorly activates the BAFF receptor.
Significance: Heteromers should be taken into account when evaluating the physiology or pharmacological inhibition of BAFF and APRIL.</description><subject>Animals</subject><subject>APRIL</subject><subject>B-Cell Activating Factor - chemistry</subject><subject>B-Cell Activating Factor - genetics</subject><subject>B-Cell Activating Factor - metabolism</subject><subject>B-Cell Activation Factor Receptor - genetics</subject><subject>B-Cell Activation Factor Receptor - metabolism</subject><subject>B-Cell Maturation Antigen - genetics</subject><subject>B-Cell Maturation Antigen - metabolism</subject><subject>BAFF</subject><subject>cytokine</subject><subject>Dimerization</subject><subject>heteromers</subject><subject>Humans</subject><subject>Immunology</subject><subject>Ligands</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Models, Molecular</subject><subject>Protein Binding</subject><subject>protein engineering</subject><subject>receptor</subject><subject>Signal Transduction</subject><subject>signaling</subject><subject>Transmembrane Activator and CAML Interactor Protein - genetics</subject><subject>Transmembrane Activator and CAML Interactor Protein - metabolism</subject><subject>Tumor Necrosis Factor Ligand Superfamily Member 13 - chemistry</subject><subject>Tumor Necrosis Factor Ligand Superfamily Member 13 - genetics</subject><subject>Tumor Necrosis Factor Ligand Superfamily Member 13 - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kcFvFCEUh4nR2LV69mY4epktzMAwXEy2q9s2WWPT1sQbYZjHLnUWVmCb7H9f1q2NHuQCL3zv9wgfQu8pmVIi2Nl9b6ZfKeXTtqWM8BdoQknXVA2nP16iCSE1rWTNuxP0JqV7UhaT9DU6qbnkTSe7CfK3OTizdmEDOe5xsPgSMsRSRmfw-WyxwNoPeHZ9c7XE830OP52HhD87k3Uuh7s1uIhvwMA2h4jPnR-cX_3uuXUrr8dDdR3DFmJ2kN6iV1aPCd497afo--LL3fyyWn67uJrPlpVhrMmVsKInNdfAwUrC-oZaURsAwtteD6Yn3BLRikETyYXlTa9rDsZYIwbCBWHNKfp0zN3u-g0MBnyOelTb6DY67lXQTv17491arcKDYqyjdUNLwMengBh-7SBltXHJwDhqD2GXFG0l5VIyURf07IiaGFKKYJ_HUKIOllSxpA6W1NFS6fjw9-ue-T9aCiCPAJQ_enAQVTIOvIHBRTBZDcH9N_wRXymjgw</recordid><startdate>20150626</startdate><enddate>20150626</enddate><creator>Schuepbach-Mallepell, Sonia</creator><creator>Das, Dolon</creator><creator>Willen, Laure</creator><creator>Vigolo, Michele</creator><creator>Tardivel, Aubry</creator><creator>Lebon, Luc</creator><creator>Kowalczyk-Quintas, Christine</creator><creator>Nys, Josquin</creator><creator>Smulski, Cristian</creator><creator>Zheng, Timothy S.</creator><creator>Maskos, Klaus</creator><creator>Lammens, Alfred</creator><creator>Jiang, Xuliang</creator><creator>Hess, Henry</creator><creator>Tan, Seng-Lai</creator><creator>Schneider, Pascal</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20150626</creationdate><title>Stoichiometry of Heteromeric BAFF and APRIL Cytokines Dictates Their Receptor Binding and Signaling Properties</title><author>Schuepbach-Mallepell, Sonia ; Das, Dolon ; Willen, Laure ; Vigolo, Michele ; Tardivel, Aubry ; Lebon, Luc ; Kowalczyk-Quintas, Christine ; Nys, Josquin ; Smulski, Cristian ; Zheng, Timothy S. ; Maskos, Klaus ; Lammens, Alfred ; Jiang, Xuliang ; Hess, Henry ; Tan, Seng-Lai ; Schneider, Pascal</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c443t-7f7b025ae5ef904b31f72cee056badcb05f0767da0957f53ba25eccfc7d057043</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>APRIL</topic><topic>B-Cell Activating Factor - chemistry</topic><topic>B-Cell Activating Factor - genetics</topic><topic>B-Cell Activating Factor - metabolism</topic><topic>B-Cell Activation Factor Receptor - genetics</topic><topic>B-Cell Activation Factor Receptor - metabolism</topic><topic>B-Cell Maturation Antigen - genetics</topic><topic>B-Cell Maturation Antigen - metabolism</topic><topic>BAFF</topic><topic>cytokine</topic><topic>Dimerization</topic><topic>heteromers</topic><topic>Humans</topic><topic>Immunology</topic><topic>Ligands</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Models, Molecular</topic><topic>Protein Binding</topic><topic>protein engineering</topic><topic>receptor</topic><topic>Signal Transduction</topic><topic>signaling</topic><topic>Transmembrane Activator and CAML Interactor Protein - genetics</topic><topic>Transmembrane Activator and CAML Interactor Protein - metabolism</topic><topic>Tumor Necrosis Factor Ligand Superfamily Member 13 - chemistry</topic><topic>Tumor Necrosis Factor Ligand Superfamily Member 13 - genetics</topic><topic>Tumor Necrosis Factor Ligand Superfamily Member 13 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schuepbach-Mallepell, Sonia</creatorcontrib><creatorcontrib>Das, Dolon</creatorcontrib><creatorcontrib>Willen, Laure</creatorcontrib><creatorcontrib>Vigolo, Michele</creatorcontrib><creatorcontrib>Tardivel, Aubry</creatorcontrib><creatorcontrib>Lebon, Luc</creatorcontrib><creatorcontrib>Kowalczyk-Quintas, Christine</creatorcontrib><creatorcontrib>Nys, Josquin</creatorcontrib><creatorcontrib>Smulski, Cristian</creatorcontrib><creatorcontrib>Zheng, Timothy S.</creatorcontrib><creatorcontrib>Maskos, Klaus</creatorcontrib><creatorcontrib>Lammens, Alfred</creatorcontrib><creatorcontrib>Jiang, Xuliang</creatorcontrib><creatorcontrib>Hess, Henry</creatorcontrib><creatorcontrib>Tan, Seng-Lai</creatorcontrib><creatorcontrib>Schneider, Pascal</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schuepbach-Mallepell, Sonia</au><au>Das, Dolon</au><au>Willen, Laure</au><au>Vigolo, Michele</au><au>Tardivel, Aubry</au><au>Lebon, Luc</au><au>Kowalczyk-Quintas, Christine</au><au>Nys, Josquin</au><au>Smulski, Cristian</au><au>Zheng, Timothy S.</au><au>Maskos, Klaus</au><au>Lammens, Alfred</au><au>Jiang, Xuliang</au><au>Hess, Henry</au><au>Tan, Seng-Lai</au><au>Schneider, Pascal</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Stoichiometry of Heteromeric BAFF and APRIL Cytokines Dictates Their Receptor Binding and Signaling Properties</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2015-06-26</date><risdate>2015</risdate><volume>290</volume><issue>26</issue><spage>16330</spage><epage>16342</epage><pages>16330-16342</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>The closely related TNF family ligands B cell activation factor (BAFF) and aproliferation-inducing ligand (APRIL) serve in the generation and maintenance of mature B-lymphocytes. Both BAFF and APRIL assemble as homotrimers that bind and activate several receptors that they partially share. However, heteromers of BAFF and APRIL that occur in patients with autoimmune diseases are incompletely characterized. The N and C termini of adjacent BAFF or APRIL monomers are spatially close and can be linked to create single-chain homo- or hetero-ligands of defined stoichiometry. Similar to APRIL, heteromers consisting of one BAFF and two APRILs (BAA) bind to the receptors B cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) but not to the BAFF receptor (BAFFR). Heteromers consisting of one APRIL and two BAFF (ABB) bind to TACI and BCMA and weakly to BAFFR in accordance with the analysis of the receptor interaction sites in the crystallographic structure of ABB. Receptor binding correlated with activity in reporter cell line assays specific for BAFFR, TACI, or BCMA. Single-chain BAFF (BBB) and to a lesser extent single-chain ABB, but not APRIL or single-chain BAA, rescued BAFFR-dependent B cell maturation in BAFF-deficient mice. In conclusion, BAFF-APRIL heteromers of different stoichiometries have distinct receptor-binding properties and activities. Based on the observation that heteromers are less active than BAFF, we speculate that their physiological role might be to down-regulate BAFF activity.
Background: The B cell survival factors B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) can heteromerize.
Results: BAFF-APRIL2 and APRIL-BAFF2 heteromers have distinct receptor-binding specificities and activities.
Conclusion: BAFF-APRIL2 resembles APRIL, and APRIL-BAFF2 resembles BAFF but poorly activates the BAFF receptor.
Significance: Heteromers should be taken into account when evaluating the physiology or pharmacological inhibition of BAFF and APRIL.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>25953898</pmid><doi>10.1074/jbc.M115.661405</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | The Journal of biological chemistry, 2015-06, Vol.290 (26), p.16330-16342 |
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| language | eng |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Animals APRIL B-Cell Activating Factor - chemistry B-Cell Activating Factor - genetics B-Cell Activating Factor - metabolism B-Cell Activation Factor Receptor - genetics B-Cell Activation Factor Receptor - metabolism B-Cell Maturation Antigen - genetics B-Cell Maturation Antigen - metabolism BAFF cytokine Dimerization heteromers Humans Immunology Ligands Mice Mice, Inbred C57BL Models, Molecular Protein Binding protein engineering receptor Signal Transduction signaling Transmembrane Activator and CAML Interactor Protein - genetics Transmembrane Activator and CAML Interactor Protein - metabolism Tumor Necrosis Factor Ligand Superfamily Member 13 - chemistry Tumor Necrosis Factor Ligand Superfamily Member 13 - genetics Tumor Necrosis Factor Ligand Superfamily Member 13 - metabolism |
| title | Stoichiometry of Heteromeric BAFF and APRIL Cytokines Dictates Their Receptor Binding and Signaling Properties |
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