Developmental Cell, 7 August, 2024, DOI：https://doi.org/10.1016/j.devcel.2024.07.011

Itaconate uptake via SLC13A3 improves hepatic antibacterial innate immunity

Chao Chen, Caiyun Liu, Pengkai Sun, Zhenxing Zhang, Zhimin Wang, Ping Liu, Xinjian Li

Abstract

Itaconate is an immunoregulatory metabolite produced by the mitochondrial enzyme immune-responsive gene 1 (IRG1) in inflammatory macrophages. We recently identified an important mechanism by which itaconate is released from inflammatory macrophages. However, it remains unknown whether extracellular itaconate is taken up by non-myeloid cells to exert immunoregulatory functions. Here, we used a custom-designed CRISPR screen to identify the dicarboxylate transporter solute carrier family 13 member 3 (SLC13A3) as an itaconate importer and to characterize the role of SLC13A3 in itaconate-improved hepatic antibacterial innate immunity. Functionally, liver-specific deletion of Slc13a3 impairs hepatic antibacterial innate immunity in vivo and in vitro. Mechanistically, itaconate uptake via SLC13A3 induces transcription factor EB (TFEB)-dependent lysosomal biogenesis and subsequently improves antibacterial innate immunity in mouse hepatocytes. These findings identify SLC13A3 as a key itaconate importer in mouse hepatocytes and will aid in the development of potent itaconate-based antibacterial therapeutics.

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