title: Murine BAFF-receptor residues 168-175 are essential for optimal CD21/35 expression but dispensable for B cell survival.
abstract: BAFF-R (B cell-activating factor belonging to the tumor necrosis factor family receptor) regulates B lymphocyte survival, maturation, homeostasis, and self-tolerance through signaling mechanisms that are not completely understood. A spontaneous BAFF-R mutation, Bcmd-1, disrupts BAFF-R signaling. However, it is not clear why the Bcmd-1-encoded BAFF-R fails to adequately support B cell survival, optimal CD21/35 expression, and B-cell tolerance to dsDNA, since it is 95% identical to the wild-type (wt) BAFF-R and retains the only known signaling motif. A retrotransposon insertion in A/WySnJ strain mice generated the Bcmd-1 allele, replacing the eight C-terminal BAFF-R residues with 21 retrotransposon-encoded residues. New data reported here show that the displaced residues, previously thought to have no signaling role, are essential for optimal CD21/35 expression but contribute little to B cell survival signaling. Analysis of wt Baffr or Bcmd-1 homozygous (A/WySnJ X B6.BCL2)F2 mice confirmed that BCL2 complemented Bcmd-1 for B cell survival but not CD21/35 expression. Through in vivo retroviral transduction experiments, we show that Baffr complemented Bcmd-1 for B cell survival but not CD21/35 expression, whereas the BaffrDelta103-175 deletion mutant lacking the BAFF-R cytoplasmic domain failed to support these functions. Importantly, we show that the BaffrDelta168-175 deletion mutant lacking the retrotransposon-displaced residues, and a BaffrT170A mutant lacking a critical threonine, supported B cell survival but failed to support optimal CD21/35 expression. These data provide the first evidence for a possible bifurcation at the receptor level in the BAFF-R signaling pathway. We suggest that discrete BAFF-R cytoplasmic domains may interact with distinct downstream pathways to provide fine control over B cell survival, maturation, and tolerance induction.
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, WI 53706, United States.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mayne
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Amanna
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Hayes
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000276:immunology*; D000818:Animals; D053265:B-Cell Activation Factor Receptor / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002470:Cell Survival; D004252:DNA Mutational Analysis; D005260:Female; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000235:genetics; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry; D017434:Protein Structure, Tertiary; D017463:Receptors, Complement 3b / Q000276:immunology*; D017464:Receptors, Complement 3d / Q000276:immunology*; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D053265:B-Cell Activation Factor Receptor; D050505:Mutant Proteins; D017463:Receptors, Complement 3b; D017464:Receptors, Complement 3d