ArticleThe Journal of investigative dermatology2013
Impaired proteasome function activates GATA3 in T cells and upregulates CTLA-4: relevance for Sézary syndrome.
Article in The Journal of investigative dermatology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 45 citations in OpenAlex.
- Role of the Proteasome System in Shaping Cellular Immunological Characteristics and Its Impact in Modulating the Pathogenesis of Immune-Related Diseases.Cells, tissues, organs · 2026Review
- Adipose Tissue and Bone Marrow-Derived Mesenchymal Stem Cells are not Really the Same: Investigating the Differences in Their Immunomodulatory, Migratory, and Adhesive Profile.Biochemical genetics · 2025Article
- A novel ubiquitination-related gene signature for overall survival prediction in patients with liver hepatocellular carcinoma.Discover oncology · 2025Article
- Proteasome: Role in T Cell Function Regulation.International journal of biological sciences · 2025Review
- Immune checkpoints and ncRNAs: pioneering immunotherapy approaches for hematological malignancies.Cancer cell international · 2024Review
- Proteostasis in T cell aging.Seminars in immunology · 2023Review
- Pharmacologic targeting of Nedd8-activating enzyme reinvigorates T-cell responses in lymphoid neoplasia.Leukemia · 2023Article
- Review
- Article
- Neddylation and anti-tumor immunity.Oncotarget · 2021Article
- The immunopathogenesis and immunotherapy of cutaneous T cell lymphoma: Pathways and targets for immune restoration and tumor eradication.Journal of the American Academy of Dermatology · 2021Review
- Targeting the ubiquitination/deubiquitination process to regulate immune checkpoint pathways.Signal transduction and targeted therapy · 2021Review
- The transcription factor Zfp281 sustains CD4Cellular & molecular immunology · 2020Article
- Review
- Immune Checkpoint Molecules-Inherited Variations as Markers for Cancer Risk.Frontiers in immunology · 2020Review
- New Therapies and Immunological Findings in Cutaneous T-Cell Lymphoma.Frontiers in oncology · 2018Review
- Immune Checkpoint Inhibitors to Treat Malignant Lymphomas.Journal of immunology research · 2018Review
- Checkpoint inhibitors in hematological malignancies.Journal of hematology & oncology · 2017Review
- MicroRNA-181 contributes to downregulation of SAMHD1 expression in CD4+ T-cells derived from Sèzary syndrome patients.Leukemia research · 2017Article
- Sézary Syndrome: Clinical and Biological Aspects.Current hematologic malignancy reports · 2016Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Highly regulated expression of the negative costimulatory molecule cytotoxic T-lymphocyte antigen-4 (CTLA-4) on T cells modulates T-cell activation and proliferation. CTLA-4 is preferentially expressed in Th2 T cells, whose differentiation depends on the transcriptional regulator GATA3. Sézary syndrome (SS) is a T-cell malignancy characterized by Th2 cytokine skewing, impaired T-cell responses, and overexpression of GATA3 and CTLA-4. GATA3 is regulated by phosphorylation and ubiquitination. In SS cells, we detected increased polyubiquitinated proteins and activated GATA3. We hypothesized that proteasome dysfunction in SS T cells may lead to GATA3 and CTLA-4 overexpression. To test this hypothesis, we blocked proteasome function with bortezomib in normal T cells, and observed sustained GATA3 and CTLA-4 upregulation. The increased CTLA-4 was functionally inhibitory in a mixed lymphocyte reaction (MLR). GATA3 directly transactivated the CTLA-4 promoter, and knockdown of GATA3 messenger RNA and protein inhibited CTLA-4 induction mediated by bortezomib. Finally, knockdown of GATA3 in patient's malignant T cells suppressed CTLA-4 expression. Here we demonstrate a new T-cell regulatory pathway that directly links decreased proteasome degradation of GATA3, CTLA-4 upregulation, and inhibition of T-cell responses. We also demonstrate the requirement of the GATA3/CTLA-4 regulatory pathway in fresh neoplastic CD4+ T cells. Targeting of this pathway may be beneficial in SS and other CTLA-4-overexpressing T-cell neoplasms.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.