A Common Druggable Defect in Regulatory T Cells from Patients with Autoimmunity
| Autor: | Clarence R Hurt, Linda Yip, Luis Soares, Garrison C. Fathman |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Ubiquitin-Protein Ligases
Immunology Drug Evaluation Preclinical Ubiquitin-Activating Enzymes medicine.disease_cause T-Lymphocytes Regulatory Autoimmune Diseases Autoimmunity Mice Ubiquitin STAT5 Transcription Factor medicine Animals Humans Immunology and Allergy SOCS3 IL-2 receptor Phosphorylation Autoimmune disease biology Gene Expression Profiling Ubiquitination Receptors Interleukin-2 Janus Kinase 1 medicine.disease Ubiquitin ligase Disease Models Animal Proteolysis biology.protein Cancer research Neddylation Tyrosine kinase Immunosuppressive Agents Signal Transduction |
| Zdroj: | Critical Reviews in Immunology. 40:185-193 |
| ISSN: | 1040-8401 |
| Popis: | We identified a druggable defect in IL-2 receptor (IL-2R) signaling by comparing the response of regulatory T cells (Tregs) of autoimmune disease patients to that of healthy controls. This defect was in the inhibition of Treg desensitization and was shared across various autoimmune diseases. Low-dose IL-2 stimulation results in maintained pSTAT5 expression for > 4 h, allowing the Treg transcriptome for "function" to be transcribed. Tregs of autoimmune Tregs of autoimmune disease patients more rapidly terminate IL-2R signaling through STAT5. Prolonged pSTAT5 expression following IL-2R activation is mediated by blocking proteasomal degradation of pJAKl, which is associated with the IL-2RP chain. In Tregs of controls, this is accomplished by inhibiting a requisite-activating post-translational modification (neddylation) of the SOCS3/Cul5 cullin ring ligase (CRL), which normally ubiquitinates pJAKl. Many receptor-associated tyrosine kinases are desensitized by a CRL. Tregs uniquely constitutively express an E3 ligase known as the gene related to anergy in lymphocytes (GRAIL), which ubiquinates the exact lysine on the Cul5 protein that needs to be neddylated as a condition for the activation and consequent ubiquitination of pJAKl. There is a defect in this GRAIL-associated pathway of competitive inhibition of neddylation in the Tregs of autoimmune disease patients. This defect can be mitigated by the application of a small-molecule drug known as a neddylation activating enzyme inhibitor (NAEi). Low-dose IL-2 and an NAEi as a protein-drug conjugate was found to be much more effective than simply using low-dose IL-2 or a combination of low-dose IL-2 and an NAEi systemically in treating animal models of autoimmune diseases. |
| Databáze: | OpenAIRE |
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