Volume 35, No 2, Feb 2025

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 35 Issue 2, February 2025: 97-116   |  Open Access

ORIGINAL ARTICLES

Nonenzymatic lysine d-lactylation induced by glyoxalase II substrate SLG dampens inflammatory immune responses

Qihang Zhao^1,† , Qiang Wang^2,† , Qinghua Yao^3,† , Zhengdong Yang^1,† , Wenfang Li⁴ , Xiaojie Cheng¹ , Yingling Wen¹ , Rong Chen² , Junfang Xu⁵ , Xuanying Wang³ , Dexiang Qin¹ , Shuyang Zhu¹ , Liujie He¹ , Nan Li¹ , Yanfeng Wu¹ , Yizhi Yu^1,* , Xuetao Cao^1,6,7,* , Pin Wang^1,8,*

¹National Key Laboratory of Immunity & Inflammation, Second Military Medical University, Shanghai, China
²Department of Urology, People’s Hospital, Peking University, Beijing, China
³The Second Affiliated Hospital of Zhejiang Chinese Medical University, Xinhua Hospital of Zhejiang Province, Zhejiang, China
⁴Department of Emergency and Intensive Care Unit, Changzheng Hospital, Second Military Medical University, Shanghai, China
⁵Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
⁶Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China
⁷Frontier Research Center for Cell Response, Institute of Immunology, College of Life Sciences, Nankai University, Tianjin, China
⁸National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Unio n Medical College, Suzhou, Jiangsu, China
^†These authors contributed equally: Qihang Zhao, Qiang Wang, Qinghua Yao, Zhengdong Yang
Correspondence: Yizhi Yu(yuyz@immunol.org)Xuetao Cao(caoxt@immunol.org)Pin Wang(wangp@immunol.org)

Immunometabolism is critical in the regulation of immunity and inflammation; however, the mechanism of preventing aberrant activation-induced immunopathology remains largely unclear. Here, we report that glyoxalase II (GLO2) in the glycolysis branching pathway is specifically downregulated by NF-κB signaling during innate immune activation via tristetraprolin (TTP)-mediated mRNA decay. As a result, its substrate S-D-lactoylglutathione (SLG) accumulates in the cytosol and directly induces d-lactyllysine modification of proteins. This nonenzymatic lactylation by SLG is greatly facilitated by a nearby cysteine residue, as it initially reacts with SLG to form a reversible S-lactylated thiol intermediate, followed by SN-transfer of the lactyl moiety to a proximal lysine. Lactylome profiling identifies 2255 lactylation sites mostly in cytosolic proteins of activated macrophages, and global protein structure analysis suggests that proximity to a cysteine residue determines the susceptibility of lysine to SLG-mediated d-lactylation. Furthermore, lactylation is preferentially enriched in proteins involved in immune activation and inflammatory pathways, and d-lactylation at lysine 310 (K310) of RelA attenuates inflammatory signaling and NF-κB transcriptional activity to restore immune homeostasis. Accordingly, TTP-binding site mutation or overexpression of GLO2 in vivo blocks this feedback lactylation in innate immune cells and promotes inflammation, whereas genetic deficiency or pharmacological inhibition of GLO2 restricts immune activation and attenuates inflammatory immunopathology both in vitro and in vivo. Importantly, dysregulation of the GLO2/SLG/d-lactylation regulatory axis is closely associated with human inflammatory phenotypes. Overall, our findings uncover an immunometabolic feedback loop of SLG-induced nonenzymatic d-lactylation and implicate GLO2 as a promising target for combating clinical inflammatory disorders.

https://doi.org/10.1038/s41422-024-01060-w

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