Immuno-suppressive function of nucleus-transducible BAF57-ΔPH in T cell activation via degradation of endogenous BAF57

Jae Seung Moon; Hong Jai Lee; Chun Chang Ho; Jin Su Shin; Sankar Ghosh; Jung Ho Kim; Sang Kyou Lee

doi:10.1007/s12185-018-2491-6

Immuno-suppressive function of nucleus-transducible BAF57-ΔPH in T cell activation via degradation of endogenous BAF57

Jae Seung Moon, Hong Jai Lee, Chun Chang Ho, Jin Su Shin, Sankar Ghosh, Jung Ho Kim, Sang Kyou Lee

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

2 Citations (Scopus)

Abstract

The BAF57 subunit, an indispensable member of the BAF complex, is functionally implicated in apoptosis, cell cycle, and T cell development through chromosomal remodeling. However, the precise roles of BAF57 in the T cell receptor (TcR)-mediated signaling pathway have not been elucidated. In this study, a nucleus-transducible form of BAF57, absent the proline-rich and HMG domains (ntBAF57-ΔPH), was generated to interfere with the interaction between BAF57 and its binding protein, BAF155. ntBAF57-ΔPH was effectively delivered into mouse CD4⁺ T cells in a dose- and time-dependent manner, without cellular toxicity. Inhibition of T cell activation by ntBAF57-ΔPH was mediated by its disruption of the interaction between BAF155 and BAF57, leading to the degradation of endogenous BAF57 and BAF155. This phenomenon led to alterations in gene expression similar to those associated with Ciclosporin A treatment. In vivo administration of ntBAF57-ΔPH enhanced survival rate of sepsis-induced mice and reduced the LPS-induced secretion of pro-inflammatory cytokines and the expression of endogenous BAF57. These results reveal a novel function of BAF57 as an essential regulator of T cell activation. ntBAF57-ΔPH represents a novel immune-suppressive drug candidate with potential uses in the treatment of autoimmunity and graft rejection.

Original language	English
Pages (from-to)	375-383
Number of pages	9
Journal	International Journal of Hematology
Volume	108
Issue number	4
DOIs	https://doi.org/10.1007/s12185-018-2491-6
Publication status	Published - 2018 Oct 1

Bibliographical note

Funding Information:
This work was partially supported by the research grant from Good T Cells; the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF-2017R1A2A1A17069807); Global Research Laboratory (GRL) Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2016K1A1A2912755). In addition, this work was supported in part by the Yonsei University Future-leading Research Initiative of 2015 (RMS2 2017-22-0137). We would like to thank Jee-Sang Yoon for technical assistance.

Funding Information:
Acknowledgements This work was partially supported by the research grant from Good T Cells; the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF-2017R1A2A1A17069807); Global Research Laboratory (GRL) Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2016K1A1A2912755). In addition, this work was supported in part by the Yonsei University Future-leading Research Initiative of 2015 (RMS2 2017-22-0137). We would like to thank Jee-Sang Yoon for technical assistance.

Publisher Copyright:
© 2018, The Japanese Society of Hematology.

All Science Journal Classification (ASJC) codes

Hematology

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10.1007/s12185-018-2491-6

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@article{4db9340331b34cd0a2cfefaabdb27391,

title = "Immuno-suppressive function of nucleus-transducible BAF57-ΔPH in T cell activation via degradation of endogenous BAF57",

abstract = "The BAF57 subunit, an indispensable member of the BAF complex, is functionally implicated in apoptosis, cell cycle, and T cell development through chromosomal remodeling. However, the precise roles of BAF57 in the T cell receptor (TcR)-mediated signaling pathway have not been elucidated. In this study, a nucleus-transducible form of BAF57, absent the proline-rich and HMG domains (ntBAF57-ΔPH), was generated to interfere with the interaction between BAF57 and its binding protein, BAF155. ntBAF57-ΔPH was effectively delivered into mouse CD4+ T cells in a dose- and time-dependent manner, without cellular toxicity. Inhibition of T cell activation by ntBAF57-ΔPH was mediated by its disruption of the interaction between BAF155 and BAF57, leading to the degradation of endogenous BAF57 and BAF155. This phenomenon led to alterations in gene expression similar to those associated with Ciclosporin A treatment. In vivo administration of ntBAF57-ΔPH enhanced survival rate of sepsis-induced mice and reduced the LPS-induced secretion of pro-inflammatory cytokines and the expression of endogenous BAF57. These results reveal a novel function of BAF57 as an essential regulator of T cell activation. ntBAF57-ΔPH represents a novel immune-suppressive drug candidate with potential uses in the treatment of autoimmunity and graft rejection.",

author = "Moon, {Jae Seung} and Lee, {Hong Jai} and Ho, {Chun Chang} and Shin, {Jin Su} and Sankar Ghosh and Kim, {Jung Ho} and Lee, {Sang Kyou}",

note = "Funding Information: This work was partially supported by the research grant from Good T Cells; the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF-2017R1A2A1A17069807); Global Research Laboratory (GRL) Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2016K1A1A2912755). In addition, this work was supported in part by the Yonsei University Future-leading Research Initiative of 2015 (RMS2 2017-22-0137). We would like to thank Jee-Sang Yoon for technical assistance. Funding Information: Acknowledgements This work was partially supported by the research grant from Good T Cells; the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF-2017R1A2A1A17069807); Global Research Laboratory (GRL) Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2016K1A1A2912755). In addition, this work was supported in part by the Yonsei University Future-leading Research Initiative of 2015 (RMS2 2017-22-0137). We would like to thank Jee-Sang Yoon for technical assistance. Publisher Copyright: {\textcopyright} 2018, The Japanese Society of Hematology.",

year = "2018",

month = oct,

day = "1",

doi = "10.1007/s12185-018-2491-6",

language = "English",

volume = "108",

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journal = "International Journal of Hematology",

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T1 - Immuno-suppressive function of nucleus-transducible BAF57-ΔPH in T cell activation via degradation of endogenous BAF57

AU - Moon, Jae Seung

AU - Lee, Hong Jai

AU - Ho, Chun Chang

AU - Shin, Jin Su

AU - Ghosh, Sankar

AU - Kim, Jung Ho

AU - Lee, Sang Kyou

N1 - Funding Information: This work was partially supported by the research grant from Good T Cells; the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF-2017R1A2A1A17069807); Global Research Laboratory (GRL) Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2016K1A1A2912755). In addition, this work was supported in part by the Yonsei University Future-leading Research Initiative of 2015 (RMS2 2017-22-0137). We would like to thank Jee-Sang Yoon for technical assistance. Funding Information: Acknowledgements This work was partially supported by the research grant from Good T Cells; the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF-2017R1A2A1A17069807); Global Research Laboratory (GRL) Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2016K1A1A2912755). In addition, this work was supported in part by the Yonsei University Future-leading Research Initiative of 2015 (RMS2 2017-22-0137). We would like to thank Jee-Sang Yoon for technical assistance. Publisher Copyright: © 2018, The Japanese Society of Hematology.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - The BAF57 subunit, an indispensable member of the BAF complex, is functionally implicated in apoptosis, cell cycle, and T cell development through chromosomal remodeling. However, the precise roles of BAF57 in the T cell receptor (TcR)-mediated signaling pathway have not been elucidated. In this study, a nucleus-transducible form of BAF57, absent the proline-rich and HMG domains (ntBAF57-ΔPH), was generated to interfere with the interaction between BAF57 and its binding protein, BAF155. ntBAF57-ΔPH was effectively delivered into mouse CD4+ T cells in a dose- and time-dependent manner, without cellular toxicity. Inhibition of T cell activation by ntBAF57-ΔPH was mediated by its disruption of the interaction between BAF155 and BAF57, leading to the degradation of endogenous BAF57 and BAF155. This phenomenon led to alterations in gene expression similar to those associated with Ciclosporin A treatment. In vivo administration of ntBAF57-ΔPH enhanced survival rate of sepsis-induced mice and reduced the LPS-induced secretion of pro-inflammatory cytokines and the expression of endogenous BAF57. These results reveal a novel function of BAF57 as an essential regulator of T cell activation. ntBAF57-ΔPH represents a novel immune-suppressive drug candidate with potential uses in the treatment of autoimmunity and graft rejection.

AB - The BAF57 subunit, an indispensable member of the BAF complex, is functionally implicated in apoptosis, cell cycle, and T cell development through chromosomal remodeling. However, the precise roles of BAF57 in the T cell receptor (TcR)-mediated signaling pathway have not been elucidated. In this study, a nucleus-transducible form of BAF57, absent the proline-rich and HMG domains (ntBAF57-ΔPH), was generated to interfere with the interaction between BAF57 and its binding protein, BAF155. ntBAF57-ΔPH was effectively delivered into mouse CD4+ T cells in a dose- and time-dependent manner, without cellular toxicity. Inhibition of T cell activation by ntBAF57-ΔPH was mediated by its disruption of the interaction between BAF155 and BAF57, leading to the degradation of endogenous BAF57 and BAF155. This phenomenon led to alterations in gene expression similar to those associated with Ciclosporin A treatment. In vivo administration of ntBAF57-ΔPH enhanced survival rate of sepsis-induced mice and reduced the LPS-induced secretion of pro-inflammatory cytokines and the expression of endogenous BAF57. These results reveal a novel function of BAF57 as an essential regulator of T cell activation. ntBAF57-ΔPH represents a novel immune-suppressive drug candidate with potential uses in the treatment of autoimmunity and graft rejection.

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Immuno-suppressive function of nucleus-transducible BAF57-ΔPH in T cell activation via degradation of endogenous BAF57

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