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 RIS Download
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