title: Mutation of the BAFF furin cleavage site impairs B-cell homeostasis and antibody responses.
abstract: B-cell-activating factor of the TNF family (BAFF)/BLyS contributes to B-cell homeostasis and function in the periphery. BAFF is expressed as a membrane-bound protein or released by proteolytic cleavage, but the functional importance of this processing event is poorly understood. Mice expressing BAFF with a mutated furin consensus cleavage site, i.e. furin-mutant BAFF (fmBAFF), were not different from BAFF-deficient mice with regard to their B-cell populations and responses to immunization. It is however noteworthy that an alternative processing event releases some soluble BAFF in fmBAFF mice. Mild overexpression (∼ 5-fold) of fmBAFF alone generated intermediate levels of B cells without improving humoral responses to immunization. Processed BAFF was however important for B-cell homeostasis, as peripheral B-cell populations and antibody responses were readily restored by administration of soluble BAFF trimers in BAFF-deficient mice. However, the rescue of CD23 expression in B cells of BAFF-deficient mice required both soluble BAFF trimers and fmBAFF, or a polymeric form of soluble BAFF (BAFF 60-mer). These results point to a predominant role of processed BAFF for B-cell homeostasis and function, and indicate possible accessory roles for membrane-bound BAFF.
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bossen
authors.forename: Aubry
authors.initials: A
authors.lastname: Tardivel
authors.forename: Laure
authors.initials: L
authors.lastname: Willen
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Fletcher
authors.forename: Mai
authors.initials: M
authors.lastname: Perroud
authors.forename: Friedrich
authors.initials: F
authors.lastname: Beermann
authors.forename: Antonius G
authors.initials: AG
authors.lastname: Rolink
authors.forename: Martin L
authors.initials: ML
authors.lastname: Scott
authors.forename: Fabienne
authors.initials: F
authors.lastname: Mackay
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation; D053264:B-Cell Activating Factor / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D045683:Furin / Q000737:chemistry; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012995:Solubility
chemical_list: D053264:B-Cell Activating Factor; D017931:DNA Primers; D007136:Immunoglobulins; D050505:Mutant Proteins; D012333:RNA, Messenger; C505720:Tnfsf13b protein, mouse; D045683:Furin