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

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 Heremeking, Bert Vogelstein, Pamela Ohashi, Tak W. Mak

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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.

Original languageEnglish (US)
Pages (from-to)1555-1560
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number4
DOIs
StatePublished - Jan 25 2011

ASJC Scopus subject areas

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    Su, Y. W., Hao, Z., Hirao, A., Yamamoto, K., Lin, W. J., Young, A., Duncan, G. S., Yoshida, H., Wakeham, A., Lang, P. A., Murakami, K., Heremeking, H., Vogelstein, B., Ohashi, P., & Mak, T. W. (2011). 14-3-3σ regulates B-cell homeostasis through stabilization of FOXO1. Proceedings of the National Academy of Sciences of the United States of America, 108(4), 1555-1560. https://doi.org/10.1073/pnas.1017729108