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

doi:10.1073/pnas.1017729108

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

Howard Hughes Medical Institution

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

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 language	English (US)
Pages (from-to)	1555-1560
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	108
Issue number	4
DOIs	https://doi.org/10.1073/pnas.1017729108
State	Published - Jan 25 2011

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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

Su, YW, Hao, Z, Hirao, A, Yamamoto, K, Lin, WJ, Young, A, Duncan, GS, Yoshida, H, Wakeham, A, Lang, PA, Murakami, K, Heremeking, H, Vogelstein, B, Ohashi, P & Mak, TW 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, vol. 108, no. 4, pp. 1555-1560. https://doi.org/10.1073/pnas.1017729108

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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.",

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AU - Lang, Philipp A.

AU - Murakami, Kiichi

AU - Heremeking, Heiko

AU - Vogelstein, Bert

AU - Ohashi, Pamela

AU - Mak, Tak W.

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

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