Itaconate is a lysosomal inducer that promotes antibacterial innate immunity

• Published in: Molecular cell Vol. 82; no. 15; pp. 2844 - 2857.e10
• Main Authors: Zhang, Zhenxing, Chen, Chao, Yang, Fan, Zeng, Yi-Xin, Sun, Pengkai, Liu, Ping, Li, Xinjian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.08.2022
• Subjects: alkylation; bacterial infection; innate immunity; itaconate; lysosomal biogenesis; macrophage; TFEB; itaconate; lysosomal biogenesis; innate immunity; TFEB; alkylation; macrophage; bacterial infection
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2022.05.009

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. [Display omitted] •Itaconate alkylates TFEB at Cys212•Alkylated-Cys212 disrupts mTOR/14-3-3-mediated cytosolic retention of TFEB•Itaconate promotes TFEB-dependent lysosomal biogenesis and innate immunity•TFEB alkylation deficiency increases susceptibility of mice to bacterial infection Zhang et al. report that the metabolite itaconate alkylates transcription factor TFEB, a master regulator of lysosomal biogenesis, at Cys212 to reduce its cytosolic retention modulated by mTOR/14-3-3. Itaconate-mediated alkylation activates TFEB-dependent lysosomal biogenesis, thereby facilitating the bacteria clearance during the antibacterial innate immune response.