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The phosphatase DUSP22/JKAP inhibits UBR2-mediated K63-ubiquitination and activation of Lck in TCR signaling ( Sequential regulation of Lck K63-ubiquitination and autophosphorylation by UBR2 and DUSP22/JKAP in TCR signaling)

ABSTRACT: DUSP22 (also named JKAP) is a dual-specificity phosphatase that inhibits T cell activation. Here we identified the E3 ubiquitin ligase UBR2 as an upstream activator of Lck during T-cell activation. JKAP dephosphorylated UBR2 at two residues, leading to ubiquitin-mediated UBR2 degradation. The SCF (SKP1-CUL1-βTrCP) complex induced UBR2 Lys48-linked ubiquitination at three lysine residues. Moreover, single-cell RNA sequencing analysis and UBR2 knockout showed that UBR2 increased proinflammatory cytokines. Remarkably, UBR2 induced Lys63-linked ubiquitination of Lck at two lysine residues and subsequent Lck Tyr394phosphorylation/activation in TCR signaling. Conversely, TCR-induced Lck activation and JKAP knockout-enhanced inflammatory phenotypes were attenuated by UBR2 knockout. Consistently, the UBR2-Lck interaction and Lck Lys63-linked ubiquitination were induced in peripheral blood T cells of human SLE patients. Collectively, UBR2 protein stability and UBR2-induced Lck ubiquitination/activation are inhibited by JKAP, leading to attenuation of T-cell activation and T-cell-mediated inflammation.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: ying chun shih

LAB HEAD: Tse-Hua Tan

PROVIDER: PXD043454 | Pride | 2024-01-04

REPOSITORIES: Pride

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The phosphatase DUSP22/JKAP inhibits UBR2-mediated K63-ubiquitination and activation of Lck in TCR signaling

Project description:DUSP22 (also named JKAP) is a dual-specificity phosphatase that inhibits T cell activation. Here we identified the E3 ubiquitin ligase UBR2 as an upstream activator of Lck during T-cell activation. JKAP dephosphorylated UBR2 at two residues, leading to ubiquitin-mediated UBR2 degradation. The SCF (SKP1-CUL1-βTrCP) complex induced UBR2 Lys48-linked ubiquitination at three lysine residues. Moreover, single-cell RNA sequencing analysis and UBR2 knockout showed that UBR2 increased proinflammatory cytokines. Remarkably, UBR2 induced Lys63-linked ubiquitination of Lck at two lysine residues and subsequent Lck Tyr394 phosphorylation/activation in TCR signaling. Conversely, TCR-induced Lck activation and JKAP knockout-enhanced inflammatory phenotypes were attenuated by UBR2 knockout. Consistently, the UBR2- Lck interaction and Lck Lys63-linked ubiquitination were induced in peripheral blood T cells of human SLE patients. Collectively, UBR2 protein stability and UBR2-induced Lck ubiquitination/activation are inhibited by JKAP, leading to attenuation of T-cell activation and T-cell-mediated inflammation.

2024-01-04 | PXD043490 | Pride

The phosphatase DUSP22/JKAP inhibits UBR2-mediated K63-ubiquitination and activation of Lck in TCR signaling

2024-01-04 | PXD043463 | Pride

The phosphatase DUSP22/JKAP inhibits UBR2-mediated K63-ubiquitination and activation of Lck in TCR signaling

2024-01-04 | PXD043457 | Pride

LILRA3-GFP and GFP only Transfected HEK293T cells LC-MSMS

Project description:The leukocyte immunoglobulin-like receptor A3 (LILRA3) is a soluble protein primarily expressed by peripheral blood monocytes and is abundant in sera of healthy donors. Extracellular LILRA3 is anti-inflammatory and displays neuro-regenerative functions in vitro. However, its intracellular expression, distribution and function(s) remain unknown. Using a combination of high-resolution confocal and super-resolution microscopy, we identified intracellular expression of native LILRA3 in the nucleus of peripheral blood monocytes and in vitro derived macrophages. This unexpected nuclear localisation of LILRA3 was confirmed in LILRA3-GFP transfected HEK293T cells. Western blot of proteins fractionated from primary macrophages and the transfected HEK293T cells confirmed nuclear localisation of the native and expressed LILRA3 proteins. Interestingly, most of the LILRA3 in the nucleus was in a monomeric form like the biologically active secreted protein, while those in the other cellular compartments were mixed monomeric, dimeric, and oligomeric forms. The predominant presence of monomeric LILRA3 in the nucleus was independently corroborated in transfected live HEK293T cells using number and molecular brightness (N&B) analysis method. Immunoprecipitation and Mass spectrometric peptide sequencing studies revealed that nuclear LILRA3 co-immunoprecipitated with several nuclear proteins involved in host protein synthesis machinery via direct interaction to a key multifunctional RNA binding protein, the Ewing sarcoma breakpoint region 1 protein (EWS).

2021-04-08 | PXD024602 | Pride

Lck phosphorylation status of Lck Tyr192 and Tyr192/Tyr505 mutantsLck phosphorylation status of Lck Tyr192 and Tyr192/Tyr505 mutants

Project description:Lymphocyte-specific protein tyrosine kinase (Lck) is crucial for signaling from the T cell receptor (TCR) and is controlled through tyrosine phosphorylations. Phosphorylated Tyr505 (pTyr505) promotes a closed, inactive conformation of Lck, while pTyr394 is critical for kinase activity. Additionally, pTyr192 has been suggested to regulate Lck activity by changing the specificity of the Lck Src-homology 2 (SH2) domain and/or by affecting Lck association with CD45 thus drastically increasing pTyr505. However, little is known about how pTyr192 affects endogenously expressed Lck. Here we used CRISPR/Cas9 genome editing to generate Jurkat cell lines expressing Lck Glu192 mimicking Lck pTyr192, or Lck Phe192 mimicking unphosphorylated Lck Tyr192. We confirmed that Lck Glu192 is hyperphosphorylated on Tyr505, possibly explaining reduced association of Lck Glu192 with prototypic Lck-SH2 ligands. To isolate the effect of Lck Tyr192 mutations from the effect on Lck pTyr505, we subsequently generated Jurkat cells doubly mutated on Lck Tyr192 and Lck Tyr505. Both Lck Phe192/Phe505 and Lck Glu192/Phe505 mutants co-precipitated similar amounts of binding partners. Moreover, both mutants displayed hyperphosphorylation of Tyr394. Our results indicate that CD45 is the main phosphatase controlling Lck pTyr394 in steady-state T cells. Additionally, our data demonstrate that the prototypic specificity of the Lck SH2 domain (owned by the Lck Phe192 mutants) promotes transphosphorylation of Tyr394. These observations pinpoint the fundamental role of Tyr192 in regulation of Lck activity and simultaneously reveal the most potent Lck mutants so far described

2021-04-02 | PXD014470 | Pride

Dynamics of replication-independent histone turnover in budding yeast

Project description:This SuperSeries is composed of the following subset Series: GSE6664: Ratios for unsync cells GSE6665: Ratios for G1 arrested cells (Printed array) GSE6666: Ratios for G1 arrested cells (Agilent array) GSE6667: PolII occupancy GSE6668: Nucleosome occupancy GSE6669: H3 occupancy GSE6670: Ratios for Htz1D cells (Agilent array) Keywords: SuperSeries Refer to individual Series

2010-06-11 | E-GEOD-6680 | biostudies-arrayexpress

Ratios for G1 arrested cells (Printed array)

Project description:Chromatin plays roles in processes governed by different time scales. To assay the dynamic behaviour of chromatin in living cells, we used genomic tiling arrays to measure histone H3 turnover in G1-arrested S. cerevisiae at single-nucleosome resolution over 4% of the genome, and over the entire genome at lower (~265 bp) resolution. We find that nucleosomes at promoters are replaced more rapidly than at coding regions, and that replacement rates over coding regions correlate with polymerase density. In addition, rapid histone turnover is found at known chromatin boundary elements. These results suggest that rapid histone turnover serves to functionally separate chromatin domains and prevent spread of histone states. Keywords: Chip-chip, time course, histone turnover Ratios between Gal-induced H3-Flag and constitutive H3-Myc at 5 time points for G1-arrested yeast. Hybridization to high-resolution printed arrays of ~4% of the yeast genome.

2010-06-11 | E-GEOD-6665 | biostudies-arrayexpress

Transcriptional profiling of p56lck-deficient regulatory and memory T cells

Project description:Signaling through the T cell antigen receptor is essential for the formation of regulatory T (Treg) cells in the thymus and for their involvement in antigen-directed suppression of immune responses. Using a conditional null allele of the gene encoding p56Lck we show here that T cell antigen receptor (TCR) signaling is also essential for sustaining the phenotype and homeostasis of Treg cells. Inactivation of p56Lck in Treg cells resulted in large-scale changes in their gene expression profile, blocked their capacity to suppress responses, inhibited their proliferation, and caused them to redistribute in the body. The results make clear multiple aspects of the Treg cell phenotype that are dependent on a sustained capacity to respond through their TCRs. Keywords: Genetic deficiency of p56lck Two-condition experiment: wild-type memory or regulatory T cells versus lck-deficient memory or regulatory T cells.

2010-05-22 | E-GEOD-13645 | biostudies-arrayexpress

A unique iron homeostasis regulatory circuit with reciprocal roles in Candida albicans commensalism and pathogenesis [ChIP_chip]

Project description:The mammalian gastrointestinal tract and the bloodstream are highly disparate biological niches, and yet certain commensal-pathogenic microorganisms are able to thrive in both environments. Here, we report the evolution of a unique transcription circuit in the yeast, Candida albicans, which determines its fitness in both host niches. Our comprehensive analysis of the DNA-binding proteins that regulate iron uptake by this organism suggests the evolutionary intercalation of a transcriptional activator called Sef1 between two broadly conserved transcriptional repressors, Sfu1 and Hap43. The Sef1 activator of iron uptake genes promotes virulence in a mouse model of bloodstream infection, whereas the Sfu1 repressor is dispensable for virulence but promotes gastrointestinal commensalism. We propose that the ability to alternate between genetic programs conferring resistance to iron depletion in the bloodstream versus iron toxicity in the gut may be a fundamental attribute of gastrointestinal commensal-pathogens. ChIP analyses to profile genome-wide of distribution of Sef1, Sfu1 and Hap43 in response to various iron availability. 12 independent ChIP experiments were performed on 6 biological replicates of the untagged control and 2 biological replicates each of Sef1-Myc, Sfu1-Myc, and Hap43-Myc.

2011-07-12 | E-GEOD-30591 | biostudies-arrayexpress

Signature cleavage in vitro assay of 20S and 26S proteasome using naked and ubiquitined cyclin

Project description:A systematic and comparative study of the proteolysis products generated by purified human 26S and 20S proteasome following the in vitro cleavage of non-modified (naked), mono-ubiquitinated and poly-ubiquitinated cyclin B.

2021-11-02 | PXD018711 | Pride

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