Portal de Periódicos da CAPES

14-3-3σ regulates B-cell homeostasis through stabilization of FOXO1

2011; National Academy of Sciences; Volume: 108; Issue: 4 Linguagem: Inglês

10.1073/pnas.1017729108

1091-6490

Yu‐Wen Su, Zhenyue Hao, Atsushi Hirao, Kazuo Yamamoto, Wen‐Jye Lin, Ashley Young, Gordon S. Duncan, Hiroki Yoshida, Andrew Wakeham, Philipp A. Lang, Kiichi Murakami, Heiko Hermeking, Bert Vogelstein, Pamela S. Ohashi, Tak W. Mak,

Signaling Pathways in Disease

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.