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

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.

Pubmed ID: 21205887

Authors

  • 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

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

January 25, 2011

Associated Grants

None

Mesh Terms

  • 14-3-3 Proteins
  • Adoptive Transfer
  • Animals
  • Antigens
  • Apoptosis
  • B-Lymphocytes
  • Blotting, Western
  • Cell Proliferation
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Ficoll
  • Forkhead Transcription Factors
  • Homeostasis
  • Immunoglobulin G
  • Immunoglobulin M
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Binding
  • Receptors, Antigen, B-Cell
  • Reverse Transcriptase Polymerase Chain Reaction
  • Trinitrobenzenes