title: EndoU is a novel regulator of AICD during peripheral B cell selection.
abstract: Balanced transmembrane signals maintain a competent peripheral B cell pool limited in self-reactive B cells that may produce pathogenic autoantibodies. To identify molecules regulating peripheral B cell survival and tolerance to self-antigens (Ags), a gene modifier screen was performed with B cells from CD22-deficient C57BL/6 (CD22(-/-[B6])) mice that undergo activation-induced cell death (AICD) and fail to up-regulate c-Myc expression after B cell Ag receptor ligation. Likewise, lysozyme auto-Ag-specific B cells in Ig(Tg) hen egg lysozyme (HEL) transgenic mice inhabit the spleen but undergo AICD after auto-Ag encounter. This gene modifier screen identified EndoU, a single-stranded RNA-binding protein of ancient origin, as a major regulator of B cell survival in both models. EndoU gene disruption prevents AICD and normalizes c-Myc expression. These findings reveal that EndoU is a critical regulator of an unexpected and novel RNA-dependent pathway controlling peripheral B cell survival and Ag responsiveness that may contribute to peripheral B cell tolerance.
authors.affiliation: Department of Immunology and 2 Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Poe
authors.forename: Evgueni I
authors.initials: EI
authors.lastname: Kountikov
authors.forename: Jacquelyn M
authors.initials: JM
authors.lastname: Lykken
authors.forename: Abirami
authors.initials: A
authors.lastname: Natarajan
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Marchuk
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Tedder
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000502:physiology; D015153:Blotting, Western; D016923:Cell Death / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005453:Fluorescence; D020869:Gene Expression Profiling; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016271:Proto-Oncogene Proteins c-myc; D040641:Quantitative Trait Loci / Q000235:genetics; D017634:Self Tolerance / Q000276:immunology*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*; D000086842:Uridylate-Specific Endoribonucleases
chemical_list: C497868:Cd22 protein, mouse; D017931:DNA Primers; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D051918:Sialic Acid Binding Ig-like Lectin 2; D004720:Endonucleases; C475860:Endou protein, mouse; D000086842:Uridylate-Specific Endoribonucleases