PXD011164-1

PXD011164 is an original dataset announced via ProteomeXchange.

Title	Nemo-like kinase drives Foxp3 stability and is critical for maintenance of immune tolerance by regulatory T cells
Description	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 (NLKTREG) 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. Pharmacological manipulation of this phosphorylation-ubiquitination axis may provide therapeutic opportunities for regulating TREG cell function, for example during cancer immunotherapy.
HostingRepository	PRIDE
AnnounceDate	2019-09-02
AnnouncementXML	Submission_2019-09-02_06:00:09.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Harmjan Vos
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2018-09-24 01:39:42	ID requested
⏵ 1	2019-09-02 06:00:10	announced
2	2024-10-22 04:14:41	announced	2024-10-22: Updated project metadata.

Fleskens V, Minutti CM, Wu X, Wei P, Pals CEGM, McCrae J, Hemmers S, Groenewold V, Vos HJ, Rudensky A, Pan F, Li H, Zaiss DM, Coffer PJ, Nemo-like Kinase Drives Foxp3 Stability and Is Critical for Maintenance of Immune Tolerance by Regulatory T Cells. Cell Rep, 26(13):3600-3612.e6(2019) [pubmed]

curator keyword: Biological

submitter keyword: NLK, Foxp3, phosphorylation, regulatory T cell, NLK, TCR, ubiquitination, immune tolerance

Paul J. Coffer
contact affiliation	Center for Molecular Medicine & Division of Pediatrics, Regenerative Medicine Center, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
contact email	pcoffer@umcutrecht.nl
lab head
Harmjan Vos
contact affiliation	University Medical Center Utrecht Dept. Molecular Cancer Research
contact email	h.r.vos-3@umcutrecht.nl
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2019/09/PXD011164

PRIDE project URI

• PRIDE
  1. PXD011164
     1. Label: PRIDE project
     2. Name: Nemo-like kinase drives Foxp3 stability and is critical for maintenance of immune tolerance by regulatory T cells