Itaconate is a lysosomal inducer that promotes antibacterial innate immunity
Itaconate is a lysosomal inducer that promotes antibacterial innate immunity
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DOI：
10.1016/j.molcel.2022.05.009
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发表时间：
2022-08-04
期刊：
影响因子：
16
通讯作者：
Li, Xinjian
中科院分区：
文献类型：
--
作者：
Zhang, Zhenxing;Chen, Chao;Li, Xinjian
溶酶体是巨噬细胞中杀死入侵细菌的主要细胞器。然而，细菌感染后溶酶体生物合成的确切机制仍然是个谜。我们在这里证明，LPS刺激增加IRG 1依赖的衣康酸生产，促进溶酶体生物合成通过激活转录因子，TFEB。在机制上，衣康酸盐直接在半胱氨酸212（小鼠中的Cys 270）处烷基化人TFEB，以通过拮抗mTOR介导的磷酸化和胞质保留来诱导其核定位。在功能上，通过IRG 1/Irg 1敲除或表达烷基化缺陷的TFEB突变体来废除衣康酸合成损害了巨噬细胞的体外抗菌能力。此外，含有烷基化缺陷型TFEB突变体的敲入小鼠显示出对鼠伤寒沙门氏菌感染的易感性升高，而OI（一种细胞可渗透的衣康酸衍生物）的体内治疗限制了炎症。我们的研究确定衣康酸作为一种内源性代谢产物，在巨噬细胞中作为溶酶体诱导剂响应细菌感染，这意味着衣康酸在治疗人类细菌感染的潜在治疗效用。
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.