14-3-3sigma regulates B-cell homeostasis through stabilization of FOXO1.
Journal:
Proc. Natl. Acad. Sci. U.S.A. 2011 JanAuthors:
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 secret
...[more]ion 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.[less]
Mesh Headings:
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