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Cited by 49T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisSignaling Pathways in Disease

Nemo-like Kinase Drives Foxp3 Stability and Is Critical for Maintenance of Immune Tolerance by Regulatory T Cells

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Fleskens, Veerle, Minutti, Carlos M., Wu, Xingmei, Wei, Ping, Pals, Cornelieke E.G.M., McCrae, James, Hemmers, Saskia, Groenewold, Vincent +6 more·2019·Cell Reports
DOI 10.1016/j.celrep.2019.02.087PMC PMC6444001
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Abstract

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 the 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 T REG cells can be regulated by a TGF-β activated kinase 1 (TAK1)-Nemo-like kinase (NLK) signaling pathway. NLK interacts and phosphorylates Foxp3 in T REG cells, resulting in the stabilization of protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase. Conditional T REG cell NLK-knockout (NLK ΔTREG ) results in decreased T REG cell-mediated immunosuppression in vivo , and NLK-deficient T REG 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 the stabilization of protein levels, thereby maintaining T REG cell suppressive function.

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  • Foxp3 transcriptional activity was regulated by TAK1-NLK-mediated phosphorylation, and NLK activity was required to maintain homeostatic Treg cell numbers.

    “In detail, Foxp3 transcriptional activity was regulated by TAK1-NLK-mediated phosphorylation, and NLK activity was required to maintain homeostatic Treg cell numbers.”

    From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [46]

    The Discussion states that TAK1–NLK-mediated phosphorylation modulates Foxp3 transcriptional activity. In Results (“TREG Cell-Specific NLK Deficiency Results in Inflammation”; page unavailable), young NLK-deficient mice had comparable percentages of Foxp3+ Treg cells, while that population declined with age. The authors attribute the decline to reduced Foxp3 protein stability, not reduced Treg survival or proliferation, so the claim that NLK is required to maintain homeostatic Treg cell numbers overstates the finding. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • NLK activity is necessary to regulate Treg cell-mediated immunosuppression.

    “Furthermore, a colitis mouse model was used to demonstrate that NLK activity is necessary to regulate Treg cell-mediated immunosuppression [46].”

    From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [46]

  • Deletion of NLK in regulatory T-cells (Tregs) using FoxP3Cre mice showed that TAK1 and NLK regulated Treg cell suppressive capacity by modifying the Foxp3 protein.

    “Deletion of NLK in regulatory T-cells (Tregs) by using FoxP3Cre mice showed that TAK1 and NLK regulated Treg cell suppressive capacity by modifying the Foxp3 protein.”

    From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [46]

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Authors
Fleskens, V., Minutti, C. M., Wu, X., Wei, P., Pals, C. E. G. M., McCrae, J., Hemmers, S., Groenewold, V., Vos, H.-J., Rudensky, A., Pan, F., Li, H., Zaiss, D. M., & Coffer, P. J.
Affiliations
  • Utrecht University (NL)
  • University of Edinburgh (GB)
  • Shanghai Medical College of Fudan University (CN)
  • Children's Hospital of Chongqing Medical University (CN)
  • Memorial Sloan Kettering Cancer Center (US)
  • Johns Hopkins University (US)
Corresponding author
  • Li, Huabin
  • Zaiss, Dietmar M.
  • Coffer, Paul J.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2019-03
Volume
26
Issue
13
Pages
3600-3612.e6
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2019.02.087
PMC
PMC6444001
OpenAlex
W2924837719
Cited by
49
References
5
Citations by year
2026: 8 · 2025: 1 · 2024: 7 · 2023: 4 · 2022: 10 · 2021: 7 · 2020: 9 · 2019: 3
FWCI
2.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
Funders
  • Medical Research Council (MR/M011755/1, MR/M018911/1)
  • European Commission (CIG-631413)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (184.032.201)
  • National Institutes of Health (R01AI137046, RO1AI089830, RO1AI099300)
  • Science and Technology Commission of Shanghai Municipality (16410723600)
  • U.S. Department of Defense (PC130767)
  • Dutch Arthritis Association
  • Melanoma Research Alliance
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
Nemo-like kinase, Foxp3, regulatory T cells, TAK1 signaling, protein phosphorylation, protein stability, T cell activation, T cell receptor signaling, immune tolerance, experimental autoimmune encephalomyelitis, immunosuppression
MeSH terms
MAP Kinase Kinase Kinase 7, Animals, Female, Humans, Immune Tolerance, Inflammation, Male, Mice, Inbred C57BL, Phosphorylation, Signal Transduction, MAP Kinase Kinase Kinases, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, Protein Stability, HEK293 Cells

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