Itaconate facilitates viral infection via alkylating GDI2 and retaining Rab GTPase on the membrane  

作　　者：Shulei Yin Yijie Tao Tianliang Li Chunzhen Li Yani Cui Yunyan Zhang Shenhui Yin Liyuan Zhao Panpan Hu Likun Cui Yunyang Wu Yixian He Shu Yu Jie Chen Shaoteng Lu Guifang Qiu Mengqi Song Qianshan Hou Cheng Qian Zui Zou Sheng Xu Yizhi Yu 

机构地区：[1]National Key Laboratory of Immunity and Inflammation,Naval Medical University,Shanghai 200433,China [2]School of Anesthesiology,Naval Medical University,Shanghai 200433,China [3]Department of Respiratory and Critical Care Medicine,Changzheng Hospital,Naval Medical University,Shanghai 200433,China [4]Department of Traditional Chinese Medicine,Naval Medical University,Shanghai 200433,China [5]Faculty of Anesthesiology,Changhai Hospital,Naval Medical University,Shanghai 200433,China

出　　处：《Signal Transduction and Targeted Therapy》2025年第1期420-433,共14页信号转导与靶向治疗(英文)

摘　　要：Metabolic reprogramming of host cells plays critical roles during viral infection.Itaconate,a metabolite produced from cis-aconitate in the tricarboxylic acid cycle(TCA)by immune responsive gene 1(IRG1),is involved in regulating innate immune response and pathogen infection.However,its involvement in viral infection and underlying mechanisms remain incompletely understood.Here,we demonstrate that the IRG1-itaconate axis facilitates the infections of VSV and IAV in macrophages and epithelial cells via Rab GTPases redistribution.Mechanistically,itaconate promotes the retention of Rab GTPases on the membrane via directly alkylating Rab GDP dissociation inhibitor beta(GDI2),the latter of which extracts Rab GTPases from the membrane to the cytoplasm.Multiple alkylated residues by itaconate,including cysteines 203,335,and 414 on GDI2,were found to be important during viral infection.Additionally,this effect of itaconate needs an adequate distribution of Rab GTPases on the membrane,which relies on Rab geranylgeranyl transferase(GGTase-II)-mediated geranylgeranylation of Rab GTPases.The single-cell RNA sequencing data revealed high expression of IRG1 primarily in neutrophils during viral infection.Co-cultured and in vivo animal experiments demonstrated that itaconate produced by neutrophils plays a dominant role in promoting viral infection.Overall,our study reveals that neutrophils-derived itaconate facilitates viral infection via redistribution of Rab GTPases,suggesting potential targets for antiviral therapy.

关 键 词：INVOLVEMENT GDI retaining 

分 类 号：R51[医药卫生—内科学]