ArticleProceedings of the National Academy of Sciences of the United States of America2012
Inhibition of S-phase kinase-associated protein 2 (Skp2) reprograms and converts diabetogenic T cells to Foxp3+ regulatory T cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 21 citations in OpenAlex.
- MDMX reprograms glycolysis of hepatocellular carcinoma via 14-3-3γ/FOXO1.Cell death discovery · 2025Article
- RNF213 promotes Treg cell differentiation by facilitating K63-linked ubiquitination and nuclear translocation of FOXO1.Nature communications · 2024Article
- Regulation of inflammation and immunity in sepsis by E3 ligases.Frontiers in endocrinology · 2023Review
- Transcriptomic Analysis in Marine Medaka Gill Reveals That the Hypo-Osmotic Stress Could Alter the Immune Response via the IL17 Signaling Pathway.International journal of molecular sciences · 2022Article
- Expression of proliferation-related genes in BM-MSC-treated ALL cells in hypoxia condition is regulated under the influence of epigenetic factors in-vitro.Medical oncology (Northwood, London, England) · 2022Article
- Non-classical Vitamin D Actions for Renal Protection.Frontiers in medicine · 2021Review
- The Putative Association of TOB1-AS1 Long Non-coding RNA with Immune Tolerance: A Study on Multiple Sclerosis Patients.Neuromolecular medicine · 2020Article
- 1,25-(OH)Cell communication and signaling : CCS · 2019Article
- Forkhead box transcription factors as context-dependent regulators of lymphocyte homeostasis.Nature reviews. Immunology · 2018Review
- Inhibiting Skp2 E3 Ligase Suppresses Bleomycin-Induced Pulmonary Fibrosis.International journal of molecular sciences · 2018Article
- Extracellular vesicles derived from T regulatory cells suppress T cell proliferation and prolong allograft survival.Scientific reports · 2017Article
- Ubiquitin enzymes in the regulation of immune responses.Critical reviews in biochemistry and molecular biology · 2017Review
- Gene Expression Analysis Reveals Novel Shared Gene Signatures and Candidate Molecular Mechanisms between Pemphigus and Systemic Lupus Erythematosus in CD4Frontiers in immunology · 2017Article
- Ubiquitous points of control over regulatory T cells.Journal of molecular medicine (Berlin, Germany) · 2014Review
- Induction of regulatory T cells by high-dose gp96 suppresses murine liver immune hyperactivation.PloS one · 2013Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Autoreactive pathogenic T cells (Tpaths) and regulatory T cells (Tregs) express a distinct gene profiles; however, the genes and associated genetic/signaling pathways responsible for the functional determination of Tpaths vs. Tregs remain unknown. Here we show that Skp2, an E3 ubiquitin ligase that affects cell cycle control and death, plays a critical role in the function of diabetogenic Tpaths and Tregs. Down-regulation of Skp2 in diabetogenic Tpaths converts them into Foxp3-expressing Tregs. The suppressive function of the Tpath-converted Tregs is dependent on increased production of TGF-β/IL-10, and these Tregs are able to inhibit spontaneous diabetes in NOD mice. Like naturally arising Foxp3(+) nTregs, the converted Tregs are anergic cells with decreased proliferation and activation-induced cell death. Skp2 down-regulation leads to Tpath-Treg conversion due at least in part to up-regulation of several genes involved in cell cycle control and genes in the Foxo family. Down-regulation of the cyclin-dependent kinase inhibitor p27 alone significantly attenuates the effect of Skp2 on Tpaths and reduces the suppressive function of converted Tregs; its effect is further improved with concomitant down-regulation of p21, Foxo1, and Foxo3. In comparison, Skp2 overexpression does not change Tpath function, but significantly decreases Foxp3 expression and abrogates the suppressive function of nTregs. These findings support the critical role of Skp2 in functional specification of Tpaths and Tregs, and demonstrate an important molecular mechanism mediating Skp2 function in balancing immune tolerance during autoimmune disease development.
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