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PMID: 21205887 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

14-3-3sigma regulates B-cell homeostasis through stabilization of FOXO1.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 108 ·No. 4 ·2011-01-25 ·Pages 1555-60

Su YW, Hao Z, Hirao A, Yamamoto K, Lin WJ, Young A, Duncan GS, Yoshida H, Wakeham A, Lang PA, Murakami K, Hermeking H, Vogelstein B, Ohashi P, Mak TW

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.

MeSH Terms
14-3-3 Proteins/genetics,immunology,metabolism Adoptive Transfer Animals Antigens/immunology Apoptosis/immunology B-Lymphocytes/cytology,immunology,metabolism Blotting, Western Cell Proliferation Cells, Cultured Enzyme-Linked Immunosorbent Assay Female Ficoll/analogs & derivatives,immunology Forkhead Box Protein O1 Forkhead Transcription Factors/genetics,immunology,metabolism Homeostasis/immunology Immunoglobulin G/blood Immunoglobulin M/blood Male Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Protein Binding Receptors, Antigen, B-Cell/immunology Reverse Transcriptase Polymerase Chain Reaction Trinitrobenzenes/immunology
Chemicals
14-3-3 Proteins Antigens Forkhead Box Protein O1 Forkhead Transcription Factors Foxo1 protein, mouse Immunoglobulin G Immunoglobulin M Receptors, Antigen, B-Cell Sfn protein, mouse TNP-ficoll Trinitrobenzenes Ficoll
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Su Yu-Wen
Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1.
Hao Zhenyue
Hirao Atsushi
Yamamoto Kazuo
Lin Wen-Jye
Young Ashley
Duncan Gordon S
Yoshida Hiroki
Wakeham Andrew
Lang Philipp A
Murakami Kiichi
Hermeking Heiko
Vogelstein Bert
Ohashi Pamela
Mak Tak W
References (39)
39 references, click to expand
  1. Antibody mediated suppression of secondary IgM response in nude mice against vesicular stomatitis virus.
    J Immunol. 1986 Apr 15;136(8):3057-61 PMID: 3007610
  2. 14-3-3 proteins: structure, function, and regulation.
    Annu Rev Pharmacol Toxicol. 2000;40:617-47 PMID: 10836149
  3. PI3 kinase signals BCR-dependent mature B cell survival.
    Cell. 2009 Oct 30;139(3):573-86 PMID: 19879843
  4. FOXO transcription factors at the interface between longevity and tumor suppression.
    Oncogene. 2005 Nov 14;24(50):7410-25 PMID: 16288288
  5. Regulation of neuronal cell death by MST1-FOXO1 signaling.
    J Biol Chem. 2009 Apr 24;284(17):11285-92 PMID: 19221179
  6. 14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage.
    Nature. 1999 Oct 7;401(6753):616-20 PMID: 10524633
  7. 14-3-3 Integrates prosurvival signals mediated by the AKT and MAPK pathways in ZNF198-FGFR1-transformed hematopoietic cells.
    Blood. 2007 Jul 1;110(1):360-9 PMID: 17389761
  8. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.
    Methods. 2001 Dec;25(4):402-8 PMID: 11846609
  9. Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine.
    Cell. 1996 Mar 22;84(6):889-97 PMID: 8601312
  10. Dendritic cell-independent B cell activation during acute virus infection: a role for early CCR7-driven B-T helper cell collaboration.
    J Immunol. 2007 Feb 1;178(3):1468-76 PMID: 17237395
  11. Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting.
    Biochem J. 2001 Mar 15;354(Pt 3):605-12 PMID: 11237865
  12. B-cell subsets and the mature preimmune repertoire. Marginal zone and B1 B cells as part of a "natural immune memory".
    Immunol Rev. 2000 Jun;175:70-9 PMID: 10933592
  13. 14-3-3sigma controls mitotic translation to facilitate cytokinesis.
    Nature. 2007 Mar 15;446(7133):329-32 PMID: 17361185
  14. Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity.
    Oncogene. 2005 Mar 10;24(11):1924-35 PMID: 15688030
  15. Distinct functions for the transcription factor Foxo1 at various stages of B cell differentiation.
    Nat Immunol. 2008 Dec;9(12):1388-98 PMID: 18978794
  16. B-cell apoptosis induced by antigen receptor crosslinking is blocked by a T-cell signal through CD40.
    Nature. 1993 Aug 12;364(6438):645-8 PMID: 7688865
  17. Absence of p21CIP rescues myogenic progenitor cell proliferative and regenerative capacity in Foxk1 null mice.
    J Biol Chem. 2003 Feb 7;278(6):4015-20 PMID: 12446708
  18. Induction of Mxi1-SR alpha by FOXO3a contributes to repression of Myc-dependent gene expression.
    Mol Cell Biol. 2007 Jul;27(13):4917-30 PMID: 17452451
  19. The FoxO code.
    Oncogene. 2008 Apr 7;27(16):2276-88 PMID: 18391970
  20. Peritoneal CD5+ B-1 cells have signaling properties similar to tolerant B cells.
    J Biol Chem. 2002 Aug 23;277(34):30707-15 PMID: 12070149
  21. Aberrant B cell development and immune response in mice with a compromised BCR complex.
    Science. 1996 Jun 21;272(5269):1804-8 PMID: 8650582
  22. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.
    Cell. 1999 Mar 19;96(6):857-68 PMID: 10102273
  23. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1.
    Curr Biol. 2000 Oct 5;10(19):1201-4 PMID: 11050388
  24. Antiviral protection by vesicular stomatitis virus-specific antibodies in alpha/beta interferon receptor-deficient mice.
    J Virol. 1995 Apr;69(4):2153-8 PMID: 7884863
  25. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death.
    Cell. 1997 Sep 19;90(6):1073-83 PMID: 9323135
  26. Antiviral immune responses in the absence of organized lymphoid T cell zones in plt/plt mice.
    J Immunol. 2002 Jun 15;168(12):6032-40 PMID: 12055211
  27. 14-3-3 proteins: a family of versatile molecular regulators.
    Physiol Res. 2008;57 Suppl 3:S11-21 PMID: 18481918
  28. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1.
    Nature. 2000 Apr 13;404(6779):782-7 PMID: 10783894
  29. Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling.
    Immunity. 2006 Oct;25(4):545-57 PMID: 17000121
  30. The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor.
    J Biol Chem. 2002 Apr 19;277(16):14255-65 PMID: 11777915
  31. Foxo3-/- mice demonstrate reduced numbers of pre-B and recirculating B cells but normal splenic B cell sub-population distribution.
    Int Immunol. 2009 Jul;21(7):831-42 PMID: 19502585
  32. Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty.
    J Leukoc Biol. 2003 Jun;73(6):689-701 PMID: 12773501
  33. 14-3-3sigma is a p53-regulated inhibitor of G2/M progression.
    Mol Cell. 1997 Dec;1(1):3-11 PMID: 9659898
  34. The structural basis for 14-3-3:phosphopeptide binding specificity.
    Cell. 1997 Dec 26;91(7):961-71 PMID: 9428519
  35. 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport.
    J Cell Biol. 2002 Mar 4;156(5):817-28 PMID: 11864996
  36. B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation.
    Immunity. 1997 Mar;6(3):303-13 PMID: 9075931
  37. The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation.
    Biochem J. 2004 Jun 1;380(Pt 2):297-309 PMID: 15005655
  38. Determination of lymphocyte division by flow cytometry.
    J Immunol Methods. 1994 May 2;171(1):131-7 PMID: 8176234
  39. Role of PI3K in the generation and survival of B cells.
    Immunol Rev. 2010 Sep;237(1):55-71 PMID: 20727029
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1017729108
Published
2011-01-25
Epub
2011-00-04
Pages
1555-60
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC3029705
Subset
IM
Corrections
ErratumIn
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ErratumIn
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External Links
PubMed source DOI: 10.1073/pnas.1017729108 PMC Full Text View journal details
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