Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1

Yayi Gao; Jiayou Tang; Weiqian Chen; Qiang Li; Jia Nie; Fang Lin; Qingsi Wu; Zuojia Chen; Zhimei Gao; Huimin Fan; Andy Tsun; Jijia Shen; Guihua Chen; Zhongmin Liu; Zhenkun Lou; Nancy J. Olsen; Song Guo Zheng; Bin Li

doi:10.1073/pnas.1421463112

Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1

Yayi Gao, Jiayou Tang, Weiqian Chen, Qiang Li, Jia Nie, Fang Lin, Qingsi Wu, Zuojia Chen, Zhimei Gao, Huimin Fan, Andy Tsun, Jijia Shen, Guihua Chen, Zhongmin Liu, Zhenkun Lou, Nancy J. Olsen, Song Guo Zheng, Bin Li

Oncology

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

64 Scopus citations

Abstract

Forkhead box P3 (FOXP3)-positive Treg cells are crucial for maintaining immune homeostasis. FOXP3 cooperates with its binding partners to elicit Treg cells' signature and function, but the molecular mechanisms underlying the modulation of the FOXP3 complex remain unclear. Here we report that Deleted in breast cancer 1 (DBC1) is a key subunit of the FOXP3 complex. We found that DBC1 interacts physically with FOXP3, and depletion of DBC1 attenuates FOXP3 degradation in inflammatory conditions. Treg cells from Dbc1-deficient mice were more resistant to inflammation-mediated abrogation of Foxp3 expression and function and delayed the onset and severity of experimental autoimmune encephalomyelitis and colitis in mice. These findings establish a previously unidentified mechanism regulating FOXP3 stability during inflammation and reveal a pathway for potential therapeutic modulation and intervention in inflammatory diseases.

Original language	English (US)
Pages (from-to)	E3246-E3254
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	112
Issue number	25
DOIs	https://doi.org/10.1073/pnas.1421463112
State	Published - Jun 23 2015

Keywords

Deleted in breast cancer 1
Foxp3 complex
Inflammation
Regulatory T cells

ASJC Scopus subject areas

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10.1073/pnas.1421463112

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Gao, Y., Tang, J., Chen, W., Li, Q., Nie, J., Lin, F., Wu, Q., Chen, Z., Gao, Z., Fan, H., Tsun, A., Shen, J., Chen, G., Liu, Z., Lou, Z., Olsen, N. J., Zheng, S. G., & Li, B. (2015). Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1. Proceedings of the National Academy of Sciences of the United States of America, 112(25), E3246-E3254. https://doi.org/10.1073/pnas.1421463112

Gao, Y, Tang, J, Chen, W, Li, Q, Nie, J, Lin, F, Wu, Q, Chen, Z, Gao, Z, Fan, H, Tsun, A, Shen, J, Chen, G, Liu, Z, Lou, Z, Olsen, NJ, Zheng, SG & Li, B 2015, 'Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 25, pp. E3246-E3254. https://doi.org/10.1073/pnas.1421463112

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abstract = "Forkhead box P3 (FOXP3)-positive Treg cells are crucial for maintaining immune homeostasis. FOXP3 cooperates with its binding partners to elicit Treg cells' signature and function, but the molecular mechanisms underlying the modulation of the FOXP3 complex remain unclear. Here we report that Deleted in breast cancer 1 (DBC1) is a key subunit of the FOXP3 complex. We found that DBC1 interacts physically with FOXP3, and depletion of DBC1 attenuates FOXP3 degradation in inflammatory conditions. Treg cells from Dbc1-deficient mice were more resistant to inflammation-mediated abrogation of Foxp3 expression and function and delayed the onset and severity of experimental autoimmune encephalomyelitis and colitis in mice. These findings establish a previously unidentified mechanism regulating FOXP3 stability during inflammation and reveal a pathway for potential therapeutic modulation and intervention in inflammatory diseases.",

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AU - Gao, Yayi

AU - Tang, Jiayou

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AU - Nie, Jia

AU - Lin, Fang

AU - Wu, Qingsi

AU - Chen, Zuojia

AU - Gao, Zhimei

AU - Fan, Huimin

AU - Tsun, Andy

AU - Shen, Jijia

AU - Chen, Guihua

AU - Liu, Zhongmin

AU - Lou, Zhenkun

AU - Olsen, Nancy J.

AU - Zheng, Song Guo

AU - Li, Bin

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N2 - Forkhead box P3 (FOXP3)-positive Treg cells are crucial for maintaining immune homeostasis. FOXP3 cooperates with its binding partners to elicit Treg cells' signature and function, but the molecular mechanisms underlying the modulation of the FOXP3 complex remain unclear. Here we report that Deleted in breast cancer 1 (DBC1) is a key subunit of the FOXP3 complex. We found that DBC1 interacts physically with FOXP3, and depletion of DBC1 attenuates FOXP3 degradation in inflammatory conditions. Treg cells from Dbc1-deficient mice were more resistant to inflammation-mediated abrogation of Foxp3 expression and function and delayed the onset and severity of experimental autoimmune encephalomyelitis and colitis in mice. These findings establish a previously unidentified mechanism regulating FOXP3 stability during inflammation and reveal a pathway for potential therapeutic modulation and intervention in inflammatory diseases.

AB - Forkhead box P3 (FOXP3)-positive Treg cells are crucial for maintaining immune homeostasis. FOXP3 cooperates with its binding partners to elicit Treg cells' signature and function, but the molecular mechanisms underlying the modulation of the FOXP3 complex remain unclear. Here we report that Deleted in breast cancer 1 (DBC1) is a key subunit of the FOXP3 complex. We found that DBC1 interacts physically with FOXP3, and depletion of DBC1 attenuates FOXP3 degradation in inflammatory conditions. Treg cells from Dbc1-deficient mice were more resistant to inflammation-mediated abrogation of Foxp3 expression and function and delayed the onset and severity of experimental autoimmune encephalomyelitis and colitis in mice. These findings establish a previously unidentified mechanism regulating FOXP3 stability during inflammation and reveal a pathway for potential therapeutic modulation and intervention in inflammatory diseases.

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KW - Inflammation

KW - Regulatory T cells

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Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1

Abstract

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