ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis

Itaconate is a metabolite that synthesized from cis-aconitate in mitochondria and transported into the cytosol to exert multiple regulatory effects in macrophages. However, the mechanism by which itaconate exits from macrophages remains unknown. Using a genetic screen, we reveal that itaconate is exported from cytosol to extracellular space by ATP-binding cassette transporter G2 (ABCG2) in an ATPase-dependent manner in human and mouse macrophages. Elevation of transcription factor TFEB-dependent lysosomal biogenesis and antibacterial innate immunity are observed in inflammatory macrophages with deficiency of ABCG2-mediated itaconate export. Furthermore, deficiency of ABCG2-mediated itaconate export in macrophages promotes antibacterial innate immune defense in a mouse model of S. typhimurium infection. Thus, our findings identify ABCG2-mediated itaconate export as a key regulatory mechanism that limits TFEB-dependent lysosomal biogenesis and antibacterial innate immunity in inflammatory macrophages, implying the potential therapeutic utility of blocking itaconate export in treating human bacterial infections. [Display omitted] •A custom-designed CRISPR screen identifies ABCG2 as an itaconate exporter•ABCG2 directly exports itaconate depending on its ATPase activity•ABCG2-mediated itaconate export alleviates TFEB-dependent lysosomal biogenesis•ABCG2-mediated itaconate export limits antibacterial innate immunity It has been reported that itaconate is a lysosomal inducer that promotes antibacterial innate immunity. Here, Chen et al. reveal that ATP-binding cassette transporter G2 (ABCG2) is an itaconate exporter. ABCG2-mediated itaconate export limits antibacterial innate immunity by alleviating itaconate-induced TFEB activation and lysosomal biogenesis.