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    Itaconate is a lysosomal inducer that promotes antibacterial innate immunity, Mol Cell, 3 Jun 2022

    發布時間:2022年06月03日

    Molecular Cell, 6 Jun, 2022, DOI:https://doi.org/10.1016/j.molcel.2022.05.009

    Itaconate is a lysosomal inducer that promotes antibacterial innate immunity

    Zhenxing Zhang, Chao Chen, Fan Yang, Pengkai Sun, Ping Liu, Xinjian Li

    Abstract

    Lysosomes are the main organelles in macrophages for killing invading bacteria. However, the precise mechanism underlying lysosomal biogenesis upon bacterial infection remains enigmatic. We demonstrate here that LPS stimulation increases IRG1-dependent itaconate production, which promotes lysosomal biogenesis by activating the transcription factor, TFEB. Mechanistically, itaconate directly alkylates human TFEB at cysteine 212 (Cys270 in mice) to induce its nuclear localization by antagonizing mTOR-mediated phosphorylation and cytosolic retention. Functionally, abrogation of itaconate synthesis by IRG1/Irg1 knockout or expression of an alkylation-deficient TFEB mutant impairs the antibacterial ability of macrophages in vitro. Furthermore, knockin mice harboring an alkylation-deficient TFEB mutant display elevated susceptibility to Salmonella typhimurium infection, whereas in vivo treatment of OI, a cell-permeable itaconate derivative, limits inflammation. Our study identifies itaconate as an endogenous metabolite that functions as a lysosomal inducer in macrophages in response to bacterial infection, implying the potential therapeutic utility of itaconate in treating human bacterial infection.

    文章鏈接:https://www.cell.com/molecular-cell/fulltext/S1097-2765(22)00443-9

    相關報道:http://www.acts1920.com/kyjz/zxdt/202206/t20220606_6457340.html

     

     

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