Cargando…
Global lactylome reveals lactylation-dependent mechanisms underlying T(H)17 differentiation in experimental autoimmune uveitis
Dysregulation of CD4(+) T cell differentiation is linked to autoimmune diseases. Metabolic reprogramming from oxidative phosphorylation to glycolysis and accumulation of lactate are involved in this process. However, the underlying mechanisms remain unclear. Our study showed that lactate-derived lac...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10584346/ https://www.ncbi.nlm.nih.gov/pubmed/37851814 http://dx.doi.org/10.1126/sciadv.adh4655 |
Sumario: | Dysregulation of CD4(+) T cell differentiation is linked to autoimmune diseases. Metabolic reprogramming from oxidative phosphorylation to glycolysis and accumulation of lactate are involved in this process. However, the underlying mechanisms remain unclear. Our study showed that lactate-derived lactylation regulated CD4(+) T cell differentiation. Lactylation levels in CD4(+) T cells increased with the progression of experimental autoimmune uveitis (EAU). Inhibition of lactylation suppressed T(H)17 differentiation and attenuated EAU inflammation. The global lactylome revealed the landscape of lactylated sites and proteins in the CD4(+) T cells of normal and EAU mice. Specifically, hyperlactylation of Ikzf1 at Lys(164) promoted T(H)17 differentiation by directly modulating the expression of T(H)17-related genes, including Runx1, Tlr4, interleukin-2 (IL-2), and IL-4. Delactylation of Ikzf1 at Lys(164) impaired T(H)17 differentiation. These findings exemplify how glycolysis regulates the site specificity of protein lactylation to promote T(H)17 differentiation and implicate Ikzf1 lactylation as a potential therapeutic target for autoimmune diseases. |
---|