Stoichiometry of Heteromeric BAFF and APRIL Cytokines Dictates Their Receptor Binding and Signaling Properties.

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Ressource 1Download: J. Biol. Chem.-2015-Schuepbach-Mallepell-16330-42.pdf (2759.58 [Ko])
State: Public
Version: Final published version
Serval ID
serval:BIB_0DDA43F69087
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Stoichiometry of Heteromeric BAFF and APRIL Cytokines Dictates Their Receptor Binding and Signaling Properties.
Journal
Journal of Biological Chemistry
Author(s)
Schuepbach-Mallepell S., Das D., Willen L., Vigolo M., Tardivel A., Lebon L., Kowalczyk-Quintas C., Nys J., Smulski C., Zheng T.S., Maskos K., Lammens A., Jiang X., Hess H., Tan S.L., Schneider P.
ISSN
1083-351X (Electronic)
ISSN-L
0021-9258
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
290
Number
26
Pages
16330-16342
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
The closely related TNF family ligands B cell activation factor (BAFF) and a proliferation-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.
Keywords
cytokine, immunology, protein engineering, receptor, signaling, APRIL, BAFF, heteromers
Pubmed
Web of science
Open Access
Yes
Create date
16/07/2015 11:35
Last modification date
20/08/2019 12:34
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