Deltex1 Is a Target of the Transcription Factor NFAT that Promotes T Cell Anergy

Hsiao, Huey-Wen; Liu, Wen‐Hsien; Wang, Chen-Jhe; Lo, Yu-Hsun; Wu, Yung-Hsuan; Jiang, Shinn‐Jong; Lai, Ming‐Zong

doi:10.1016/j.immuni.2009.04.017

Cited by 59 publications

(56 citation statements)

References 42 publications

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“…Knockout of DTX1 eliminates restriction in T cell activation, confers resistance to anergy induction, and results in generation of autoimmune syndromes in mice (23). DTX1 promotes the degradation of MEK kinase 1 and stimulates the expression of Cbl-b and GADD45b (23). In the current study, we found that DTX1 also targets PKCu for degradation.…”

supporting

confidence: 56%

“…We have previously demonstrated that DTX1 promotes the expression of Cblb mRNA (23). In Jurkat cells treated with A23187, knockdown of DTX1 impaired the induction of Cbl-b (Fig.…”

Section: Dtx1 Interacts With Cbl-b and Increases The Stability Of Cblmentioning

confidence: 77%

“…DTX1 mutants were generated as described previously (22,23). Full-length PKCu and Cbl-b cDNA was generated from mRNA of murine CD4 + T cell and cloned into pcDNA4-Myc-His-A and pIRES-hrGFP-1a expression vector to yield Myc-tagged and Flag-tagged proteins.…”

Section: Reagentsmentioning

confidence: 99%

“…DTX1 confers ligand-independent activation of Notch by directing the ubiquitination and endosomal entry of Notch (19)(20)(21). We recently identified DTX1 as another target of NFAT and showed that it is induced during T cell anergy (22,23). Knockout of DTX1 eliminates restriction in T cell activation, confers resistance to anergy induction, and results in generation of autoimmune syndromes in mice (23).…”

mentioning

confidence: 99%

“…We recently identified DTX1 as another target of NFAT and showed that it is induced during T cell anergy (22,23). Knockout of DTX1 eliminates restriction in T cell activation, confers resistance to anergy induction, and results in generation of autoimmune syndromes in mice (23). DTX1 promotes the degradation of MEK kinase 1 and stimulates the expression of Cbl-b and GADD45b (23).…”

mentioning

confidence: 99%

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Deltex1 Promotes Protein Kinase Cθ Degradation and Sustains Casitas B-Lineage Lymphoma Expression

Hsu

Hsiao

et al. 2014

The Journal of Immunology

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The generation of T cell anergy is associated with upregulation of ubiquitin E3 ligases including Casitas B-lineage lymphoma (Cbl-b), Itch, gene related to anergy in lymphocyte, and deltex1 (DTX1). These E3 ligases attenuate T cell activation by targeting to signaling molecules. For example, Cbl-b and Itch promote the degradation of protein kinase Cθ (PKCθ) and phospholipase C-γ1 (PLC-γ1) in anergic Th1 cells. How these anergy-associated E3 ligases coordinate during T cell anergy remains largely unknown. In the current study, we found that PKCθ and PLC-γ1 are also downregulated by DTX1. DTX1 interacted with PKCθ and PLC-γ1 and stimulated the degradation of PKCθ and PLC-γ1. T cell anergy–induced proteolysis of PKCθ was prevented in Dtx1−/− T cells, supporting the essential role of DTX1 in PKCθ downregulation. Similar to Cbl-b and Itch, DTX1 promoted monoubiquitination of PKCθ. Proteasome inhibitor did not inhibit DTX1-directed PKCθ degradation, but instead DTX1 directed the relocalization of PKCθ into the lysosomal pathway. In addition, DTX1 interacted with Cbl-b and increased the protein levels of Cbl-b. We further demonstrated the possibility that, through the downregulation of PKCθ, DTX1 prevented PKCθ-induced Cbl-b degradation and increased Cbl-b protein stability. Our results suggest the coordination between E3 ligases during T cell anergy; DTX1 acts with Cbl-b to assure a more extensive silencing of PKCθ, whereas DTX1-mediated PKCθ degradation further stabilizes Cbl-b.

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supporting

confidence: 56%

“…We have previously demonstrated that DTX1 promotes the expression of Cblb mRNA (23). In Jurkat cells treated with A23187, knockdown of DTX1 impaired the induction of Cbl-b (Fig.…”

Section: Dtx1 Interacts With Cbl-b and Increases The Stability Of Cblmentioning

confidence: 77%

Section: Reagentsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Deltex1 Promotes Protein Kinase Cθ Degradation and Sustains Casitas B-Lineage Lymphoma Expression

Hsu

Hsiao

et al. 2014

The Journal of Immunology

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The Anergy Induction of M3 Muscarinic Acetylcholine Receptor–Reactive CD4+ T Cells Suppresses Experimental Sialadenitis‐like Sjögren's Syndrome

Asashima

Tsuboi

Takahashi

et al. 2015

Arthritis & Rheumatology

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Objective. Autoreactive CD41 T cells are involved in the pathogenesis of Sj€ ogren's syndrome (SS). The aim of the present study was to clarify the dominant T cell epitopes of M3 muscarinic acetylcholine receptor (M3R) and to establish a new antigen-specific therapy for SS using an experimental mouse model.Methods. Production of cytokines from M3R-reactive CD41 T cells, after culture with various M3R peptides, was analyzed by enzyme-linked immunosorbent assay. Adoptive cell transfer was performed using splenocytes from M3R 2/2 mice that were immunized with M3R peptides or phosphate buffered saline plus H37Ra as a control. Rag1 2/2 mice were inoculated with the splenocytes and examined for the development of sialadenitis. Altered peptide ligands (APLs) of the T cell epitopes, with substitutions in amino acid residues at T cell receptor contact sites, were synthesized, and the ability of the APLs to suppress sialadenitis was evaluated. The mechanisms underlying such effects were assessed.Results. CD41 M3R-reactive T cells produced interleukin-17 (IL-17) and interferon-g (IFNg) in response to the N-terminal 1 (N1) and 1st extracellular loop peptides of M3R, and Rag1 2/2 mice that received N1-and/or 1st peptide-immunized splenocytes developed sialadenitis. Among the designed APLs, N1-APL7 (NfiS at amino acid 15) significantly suppressed IFNg production in vitro, and also suppressed sialadenitis in vivo. Levels of early growth response 2 in CD41 T cells from the cervical lymph nodes of N1-APL7-treated mice were significantly higher than those of control mice, and cell proliferation was reversed by administration of exogenous IL-2. Levels of the anergy-related molecules itchy homolog E3 ubiquitin-protein ligase, Casitas B-lineage lymphoma b, gene related to anergy in lymphocytes, and Deltex-1 were significantly higher in CD41 T cells cultured with N1-APL7. Conclusion. The major T cell epitopes were from the N1 and 1st peptide regions. Moreover, N1-APL7, selected as the antagonistic APL in vitro, also suppressed sialadenitis through the induction of anergy. This is a potentially useful strategy for regulating pathogenic T cell infiltration in SS. Sj€ ogren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration of the lacrimal and salivary glands, leading to dry eyes and dry mouth. Immunohistochemical studies have shown that most infiltrating lymphocytes around the labial salivary glands, lachrymal glands, and kidneys are CD41 a/b T cells (1). Moreover, the restricted usage of T cell receptor (TCR) a/b has been reported, suggesting that the antigen-specific immune response is the main pathologic mechanism of SS, and that non-antigen-specific immune responses are secondary mechanisms (2). Autoantigens, dumped from the damaged salivary glands, are presented by antigen-presenting cells (APCs), and autoantigen-specific T cells are activated to induce the proliferation of polyclonal T cells.

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Paxillin phosphorylation by JNK and p38 is required for NFAT activation

et al. 2012

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Paxillin is an adaptor protein associated with focal adhesion complex, and is activated by tyrosine phosphorylation through focal adhesion kinase (FAK) and Src kinase. Recent studies reveal that serine phosphorylation of paxillin by JNK and p38 MAPK is essential for cell migration or neurite extension, but their cellular targets remain unclear. In this study, we examined the requirement of paxillin phosphorylation by p38 MAPK or JNK in T-cell motility and activation using paxillin mutants at the respective phosphorylation sites, Ser85, and Ser178. (S85A)-paxillin, (S178A)-paxillin, or (S85A/S178A)-paxillin inhibited the motility of NIH/3T3 fibroblasts, but did not interfere with T-cell migration and integrin-mediated T-cell adhesion. In contrast, activation of T cells was effectively suppressed by (S85A/S178A)-paxillin. Transgenic (S85A/S178A)-paxillin expression inhibited T-cell proliferation and reduced the production of IL-2, IFN-γ, and IL-4. In searching for signals modulated by (S85A/S178A)-paxillin, we found that NFAT activation was specifically blocked by (S85A/S178A)-paxillin. This could be partly attributed to diminished stromal interaction molecule 1 (STIM1) expression and attenuated TCR-induced Ca 2+influx. Our results demonstrate that dual phosphorylation of paxillin by JNK and p38 MAPK is essential for T-cell activation and suggest that NFAT is a functional target of the JNK/p38 phosphorylated paxillin.

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Deltex1 Is a Target of the Transcription Factor NFAT that Promotes T Cell Anergy

Cited by 59 publications

References 42 publications

Deltex1 Promotes Protein Kinase Cθ Degradation and Sustains Casitas B-Lineage Lymphoma Expression

Deltex1 Promotes Protein Kinase Cθ Degradation and Sustains Casitas B-Lineage Lymphoma Expression

The Anergy Induction of M3 Muscarinic Acetylcholine Receptor–Reactive CD4+ T Cells Suppresses Experimental Sialadenitis‐like Sjögren's Syndrome

Paxillin phosphorylation by JNK and p38 is required for NFAT activation

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