4zch

Publication Abstract from PubMed

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 APRIL (BAA) bind to the receptors B cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) but not to BAFF receptor (BAFFR). Heteromers consisting of one APRIL and two BAFF (ABB) bind to TACI, 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.

Stoichiometry of heteromeric BAFF and APRIL cytokines dictate their receptor-binding and signalling properties.,Schuepbach-Mallepell S, Das D, Willen L, Vigolo M, Tardivel A, Lebon L, Kowalczyk-Quintas C, Nys J, Smulski C, Zheng TS, Maskos K, Lammens A, Jiang X, Hess H, Tan SL, Schneider P J Biol Chem. 2015 May 7. pii: jbc.M115.661405. PMID:25953898^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.