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  3. Global lactylome reveals lactylation-dependent mechanisms underlying TH17 differentiation in experimental autoimmune uveitis

Global lactylome reveals lactylation-dependent mechanisms underlying TH17 differentiation in experimental autoimmune uveitis

  • Sci Adv. 2023 Oct 20;9(42):eadh4655. doi: 10.1126/sciadv.adh4655.
Wei Fan 1 2 3 4,  Xiaotang Wang 1 2 3 4,  Shuhao Zeng 1 2 3 4,  Na Li 5,  Guoqing Wang 1 2 3 4,  Ruonan Li 1 2 3 4,  Siyuan He 1 2 3 4,  Wanqian Li 1 2 3 4,  Jiaxing Huang 1 2 3 4,  Xingran Li 1 2 3 4,  Jiangyi Liu 1 2 3 4,  Shengping Hou 1 2 3 4 6
Affiliations

Affiliations

  • 1 The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2 Chongqing Key Laboratory of Ophthalmology, Chongqing, China.
  • 3 Chongqing Eye Institute, Chongqing, China.
  • 4 Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, China.
  • 5 School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
  • 6 Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing, 100730, China.
PMID: 37851814 DOI: 10.1126/sciadv.adh4655
Abstract

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 TH17 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 Lys164 promoted TH17 differentiation by directly modulating the expression of TH17-related genes, including Runx1, TLR4, interleukin-2 (IL-2), and IL-4. Delactylation of IKZF1 at Lys164 impaired TH17 differentiation. These findings exemplify how glycolysis regulates the site specificity of protein lactylation to promote TH17 differentiation and implicate IKZF1 lactylation as a potential therapeutic target for autoimmune diseases.

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