Global lactylome reveals lactylation-dependent mechanisms underlying T_H17 differentiation in experimental autoimmune uveitis

作者全名："Fan, Wei; Wang, Xiaotang; Zeng, Shuhao; Li, Na; Wang, Guoqing; Li, Ruonan; He, Siyuan; Li, Wanqian; Huang, Jiaxing; Li, Xingran; Liu, Jiangyi; Hou, Shengping"

作者地址："[Fan, Wei; Wang, Xiaotang; Zeng, Shuhao; Wang, Guoqing; Li, Ruonan; He, Siyuan; Li, Wanqian; Huang, Jiaxing; Li, Xingran; Liu, Jiangyi; Hou, Shengping] Chongqing Med Univ, Affiliated Hosp 1, Chongqing, Peoples R China; [Fan, Wei; Wang, Xiaotang; Zeng, Shuhao; Wang, Guoqing; Li, Ruonan; He, Siyuan; Li, Wanqian; Huang, Jiaxing; Li, Xingran; Liu, Jiangyi; Hou, Shengping] Chongqing Key Lab Ophthalmol, Chongqing, Peoples R China; [Fan, Wei; Wang, Xiaotang; Zeng, Shuhao; Wang, Guoqing; Li, Ruonan; He, Siyuan; Li, Wanqian; Huang, Jiaxing; Li, Xingran; Liu, Jiangyi; Hou, Shengping] Chongqing Eye Inst, Chongqing, Peoples R China; [Fan, Wei; Wang, Xiaotang; Zeng, Shuhao; Wang, Guoqing; Li, Ruonan; He, Siyuan; Li, Wanqian; Huang, Jiaxing; Li, Xingran; Liu, Jiangyi; Hou, Shengping] Natl Clin Res Ctr Ocular Dis, Chongqing Branch, Chongqing, Peoples R China; [Li, Na] Chongqing Med Univ, Sch Basic Med Sci, Chongqing 400016, Peoples R China; [Hou, Shengping] Capital Med Univ, Beijing Tongren Hosp, Beijing Tongren Eye Ctr, Beijing Inst Ophthalmol,Beijing Ophthalmol & Visua, Beijing 100730, Peoples R China"

通信作者："Hou, SP (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Chongqing, Peoples R China.; Hou, SP (通讯作者)，Chongqing Key Lab Ophthalmol, Chongqing, Peoples R China.; Hou, SP (通讯作者)，Chongqing Eye Inst, Chongqing, Peoples R China.; Hou, SP (通讯作者)，Natl Clin Res Ctr Ocular Dis, Chongqing Branch, Chongqing, Peoples R China.; Hou, SP (通讯作者)，Capital Med Univ, Beijing Tongren Hosp, Beijing Tongren Eye Ctr, Beijing Inst Ophthalmol,Beijing Ophthalmol & Visua, Beijing 100730, Peoples R China."

来源：SCIENCE ADVANCES

ESI学科分类：Multidisciplinary

WOS号：WOS:001087790200016

JCR分区：Q1

影响因子：11.7

年份：2023

卷号：9

期号：42

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："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."

基金机构："National Natural Science Foundation Project of China [82070951, 82271078]; National Key Clinical Specialties Construction Program of China; Chongqing Branch of National Clinical Research Center for Ocular Diseases; Chongqing Key Laboratory of Ophthalmology(CSTC) [2008CA5003]; Program for Youth Innovation in Future Medicine Chongqing Medical University [W0047]"

基金资助正文："This work was supported by the National Natural Science Foundation Project of China (82070951 and 82271078), the National Key Clinical Specialties Construction Program of China, the Chongqing Branch of National Clinical Research Center for Ocular Diseases ,the Chongqing Key Laboratory of Ophthalmology(CSTC, 2008CA5003), and the Program for Youth Innovation in Future Medicine Chongqing Medical University (W0047)."