title: 14-3-3sigma regulates B-cell homeostasis through stabilization of FOXO1.
abstract: 14-3-3σ regulates cytokinesis and cell cycle arrest induced by DNA damage but its role in the immune system is unknown. Using gene-targeted 14-3-3σ-deficient (i.e., KO) mice, we studied the role of 14-3-3σ in B-cell functions. Total numbers of B cells were reduced by spontaneous apoptosis of peripheral B cells. Upon B-cell antigen receptor engagement in vitro, KO B cells did not proliferate properly or up-regulate CD86. In response to T cell-independent antigens, KO B cells showed poor secretion of antigen-specific IgM. This deficit led to increased lethality of KO mice after vesicular stomatitis virus infection. KO B cells showed elevated total FOXO transcriptional activity but also increased FOXO1 degradation. Coimmunoprecipitation revealed that endogenous 14-3-3σ protein formed a complex with FOXO1 protein. Our results suggest that 14-3-3σ maintains FOXO1 at a consistent level critical for normal B-cell antigen receptor signaling and B-cell survival.
authors.affiliation: Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Su
authors.forename: Zhenyue
authors.initials: Z
authors.lastname: Hao
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Wen-Jye
authors.initials: WJ
authors.lastname: Lin
authors.forename: Ashley
authors.initials: A
authors.lastname: Young
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Duncan
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshida
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.forename: Kiichi
authors.initials: K
authors.lastname: Murakami
authors.forename: Heiko
authors.initials: H
authors.lastname: Hermeking
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Pamela
authors.initials: P
authors.lastname: Ohashi
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005362:Ficoll / Q000031:analogs & derivatives / Q000276:immunology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006706:Homeostasis / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014301:Trinitrobenzenes / Q000276:immunology
chemical_list: D048948:14-3-3 Proteins; D000941:Antigens; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; C499130:Sfn protein, mouse; C020529:TNP-ficoll; D014301:Trinitrobenzenes; D005362:Ficoll