Nemo-like kinase drives Foxp3 stability and is critical for maintenance of immune tolerance by regulatory T cells

Veerle Fleskens; Carlos Munoz Minutti; Xingmei Wu; Ping Wei; Cornelieke E G M Pals; James McCrae; Saskia Hemmers; Vincent  Groenewold; Harm-Jan Vos; Alexander Y. Rudensky; Fan Pan; Huabin Li; Dietmar Zaiss; Paul J Coffer

doi:10.1016/j.celrep.2019.02.087

Nemo-like kinase drives Foxp3 stability and is critical for maintenance of immune tolerance by regulatory T cells

Veerle Fleskens, Carlos Munoz Minutti, Xingmei Wu, Ping Wei, Cornelieke E G M Pals, James McCrae, Saskia Hemmers, Vincent Groenewold, Harm-Jan Vos, Alexander Y. Rudensky, Fan Pan, Huabin Li, Dietmar Zaiss, Paul J Coffer

School of Biological Sciences

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

Abstract / Description of output

The Foxp3 transcription factor is a crucial determinant of both regulatory T (T_REG) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires tight regulation of Foxp3 transcriptional output, and this involves both transcriptional and post-translational regulation. Here, we show that during T cell activation, phosphorylation of Foxp3 in TREG cells can be regulated by a TGFβ Activated Kinase 1 (TAK1)-Nemo Like Kinase (NLK) signaling pathway.
NLK interacts with Foxp3 in TREG cells and directly phosphorylates Foxp3 on multiple serine residues. This phosphorylation results in stabilization of Foxp3 protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase, resulting in both reduced ubiquitination and proteasome-mediated degradation. Conditional T_REG cell NLK-knockout (NLK^ΔTREG) results in decreased T_REG cell-mediated immunosuppression in vivo and NLK-deficient TREG cell animals develop more severe experimental autoimmune encephalomyelitis. Our data suggest a molecular mechanism, in which stimulation of TCR-mediated signaling can induce a TAK1-NLK pathway to sustain Foxp3 transcriptional activity through stabilization of protein levels, thereby maintaining T_REG cell suppressive function.

Original language	English
Pages (from-to)	3600-3612
Number of pages	20
Journal	Cell Reports
Volume	26
Issue number	13
DOIs	https://doi.org/10.1016/j.celrep.2019.02.087
Publication status	Published - 26 Mar 2019

Keywords / Materials (for Non-textual outputs)

Treg cell
transcription
kinase
signaling
T cell
lymphocyte
Foxp3
phopshorylation
NLK
Ubiquitination

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10.1016/j.celrep.2019.02.087Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

Nemo-like Kinase PUB OA CC BY NC ND
© 2019 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Final published version, 2.09 MBLicence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

Epidermal growth factor receptor antagonists: Effect on regulatory T cells, and use as an adjuvant treatment for infectious disease
McCrae, J. & Gray, D.
MRC
5/08/15 → 4/08/18
Project: Research
Use of EGF-R antagonists for the treatment of infections and tumour growth
Zaiss, D.
MRC
1/04/15 → 31/03/18
Project: Research
EGF-R: Use of EGF-R antagonists for the treatment of chronic infections and tumor growth
Zaiss, D.
EU government bodies
1/03/14 → 28/02/18
Project: Research

Cite this

Fleskens, V., Munoz Minutti, C., Wu, X., Wei, P., Pals, C. E. G. M., McCrae, J., Hemmers, S., Groenewold, V., Vos, H.-J., Rudensky, A. Y., Pan, F., Li, H., Zaiss, D., & Coffer, P. J. (2019). Nemo-like kinase drives Foxp3 stability and is critical for maintenance of immune tolerance by regulatory T cells. Cell Reports, 26(13), 3600-3612. https://doi.org/10.1016/j.celrep.2019.02.087

@article{45dd70c9492143c3890d612b7b4ccb6f,

title = "Nemo-like kinase drives Foxp3 stability and is critical for maintenance of immune tolerance by regulatory T cells",

abstract = "The Foxp3 transcription factor is a crucial determinant of both regulatory T (TREG) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires tight regulation of Foxp3 transcriptional output, and this involves both transcriptional and post-translational regulation. Here, we show that during T cell activation, phosphorylation of Foxp3 in TREG cells can be regulated by a TGFβ Activated Kinase 1 (TAK1)-Nemo Like Kinase (NLK) signaling pathway. NLK interacts with Foxp3 in TREG cells and directly phosphorylates Foxp3 on multiple serine residues. This phosphorylation results in stabilization of Foxp3 protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase, resulting in both reduced ubiquitination and proteasome-mediated degradation. Conditional TREG cell NLK-knockout (NLKΔTREG) results in decreased TREG cell-mediated immunosuppression in vivo and NLK-deficient TREG cell animals develop more severe experimental autoimmune encephalomyelitis. Our data suggest a molecular mechanism, in which stimulation of TCR-mediated signaling can induce a TAK1-NLK pathway to sustain Foxp3 transcriptional activity through stabilization of protein levels, thereby maintaining TREG cell suppressive function.",

keywords = "Treg cell, transcription, kinase, signaling, T cell, lymphocyte, Foxp3, phopshorylation, NLK, Ubiquitination",

author = "Veerle Fleskens and {Munoz Minutti}, Carlos and Xingmei Wu and Ping Wei and Pals, {Cornelieke E G M} and James McCrae and Saskia Hemmers and Vincent Groenewold and Harm-Jan Vos and Rudensky, {Alexander Y.} and Fan Pan and Huabin Li and Dietmar Zaiss and Coffer, {Paul J}",

note = "To be published 26/03/2019 EN",

year = "2019",

month = mar,

day = "26",

doi = "10.1016/j.celrep.2019.02.087",

language = "English",

volume = "26",

pages = "3600--3612",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "13",

}

Fleskens, V, Munoz Minutti, C, Wu, X, Wei, P, Pals, CEGM, McCrae, J, Hemmers, S, Groenewold, V, Vos, H-J, Rudensky, AY, Pan, F, Li, H, Zaiss, D & Coffer, PJ 2019, 'Nemo-like kinase drives Foxp3 stability and is critical for maintenance of immune tolerance by regulatory T cells', Cell Reports, vol. 26, no. 13, pp. 3600-3612. https://doi.org/10.1016/j.celrep.2019.02.087

TY - JOUR

T1 - Nemo-like kinase drives Foxp3 stability and is critical for maintenance of immune tolerance by regulatory T cells

AU - Fleskens, Veerle

AU - Munoz Minutti, Carlos

AU - Wu, Xingmei

AU - Wei, Ping

AU - Pals, Cornelieke E G M

AU - McCrae, James

AU - Hemmers, Saskia

AU - Groenewold, Vincent

AU - Vos, Harm-Jan

AU - Rudensky, Alexander Y.

AU - Pan, Fan

AU - Li, Huabin

AU - Zaiss, Dietmar

AU - Coffer, Paul J

N1 - To be published 26/03/2019 EN

PY - 2019/3/26

Y1 - 2019/3/26

N2 - The Foxp3 transcription factor is a crucial determinant of both regulatory T (TREG) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires tight regulation of Foxp3 transcriptional output, and this involves both transcriptional and post-translational regulation. Here, we show that during T cell activation, phosphorylation of Foxp3 in TREG cells can be regulated by a TGFβ Activated Kinase 1 (TAK1)-Nemo Like Kinase (NLK) signaling pathway. NLK interacts with Foxp3 in TREG cells and directly phosphorylates Foxp3 on multiple serine residues. This phosphorylation results in stabilization of Foxp3 protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase, resulting in both reduced ubiquitination and proteasome-mediated degradation. Conditional TREG cell NLK-knockout (NLKΔTREG) results in decreased TREG cell-mediated immunosuppression in vivo and NLK-deficient TREG cell animals develop more severe experimental autoimmune encephalomyelitis. Our data suggest a molecular mechanism, in which stimulation of TCR-mediated signaling can induce a TAK1-NLK pathway to sustain Foxp3 transcriptional activity through stabilization of protein levels, thereby maintaining TREG cell suppressive function.

AB - The Foxp3 transcription factor is a crucial determinant of both regulatory T (TREG) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires tight regulation of Foxp3 transcriptional output, and this involves both transcriptional and post-translational regulation. Here, we show that during T cell activation, phosphorylation of Foxp3 in TREG cells can be regulated by a TGFβ Activated Kinase 1 (TAK1)-Nemo Like Kinase (NLK) signaling pathway. NLK interacts with Foxp3 in TREG cells and directly phosphorylates Foxp3 on multiple serine residues. This phosphorylation results in stabilization of Foxp3 protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase, resulting in both reduced ubiquitination and proteasome-mediated degradation. Conditional TREG cell NLK-knockout (NLKΔTREG) results in decreased TREG cell-mediated immunosuppression in vivo and NLK-deficient TREG cell animals develop more severe experimental autoimmune encephalomyelitis. Our data suggest a molecular mechanism, in which stimulation of TCR-mediated signaling can induce a TAK1-NLK pathway to sustain Foxp3 transcriptional activity through stabilization of protein levels, thereby maintaining TREG cell suppressive function.

KW - Treg cell

KW - transcription

KW - kinase

KW - signaling

KW - T cell

KW - lymphocyte

KW - Foxp3

KW - phopshorylation

KW - NLK

KW - Ubiquitination

U2 - 10.1016/j.celrep.2019.02.087

DO - 10.1016/j.celrep.2019.02.087

M3 - Article

SN - 2211-1247

VL - 26

SP - 3600

EP - 3612

JO - Cell Reports

JF - Cell Reports

IS - 13

ER -

Nemo-like kinase drives Foxp3 stability and is critical for maintenance of immune tolerance by regulatory T cells

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

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Projects

Epidermal growth factor receptor antagonists: Effect on regulatory T cells, and use as an adjuvant treatment for infectious disease

Use of EGF-R antagonists for the treatment of infections and tumour growth

EGF-R: Use of EGF-R antagonists for the treatment of chronic infections and tumor growth

Cite this