Itaconate is one of the most highly upregulated metabolites in M1-polarized macrophages. In the last 5 years, itaconate has gained significant attention due to is capacity to modulate immune responses and its inherent anti-bacterial activity. Recent studies have revealed that ATP-binding cassette transporter G2 (ABCG2)-mediated itaconate export limits macrophagic antibacterial innate immunity through alleviating itaconate-induced lysosomal biogenesis (Mol Cell 2022; Cell Metab 2024). However, the molecular mechanisms underlying itaconate taken up by non-immune cells and its biological functions remain so far mostly unclear.

On August 7, 2024, the LI Xinjian Laboratory at the Institute of Biophysics, Chinese Academy of Sciences (CAS), published online a paper entitled "Itaconate uptakevia SLC13A3 improves hepatic antibacterial innate immunity" in Developmental Cell. Using recently developed itaconate biosensor BioITA (Nat Commun 2022) as a readout, the dicarboxylate transporter SLC13A3 was screened as an itaconate importer from a custom-designed library containing thousands of gRNAs targeting genes encoding plasma membrane proteins. Next, the researchers characterized SLC13A3 as a dominant itaconate importer in hepatocytes. Importantly, they found that SLC13A3-mediated itaconate uptake by hepatocytes is required to ameliorate hepatic antibacterial innate immunity in vivo. Mechanistically, the researchers revealed that SLC13A3-mediated itaconate transport promotes TFEB-dependent lysosomal biogenesis and subsequently ameliorates antibacterial innate immunity in hepatocytes. These findings thus identify SLC13A3 as a dominant itaconate importer in hepatocytes and will aid in the development of more targeted itaconate-based antibacterial therapeutics.

Figure 1. SLC13A3 is an itaconate importer. SLC13A3-mediated itaconate uptake improves hepatic antibacterial innate immunity by activating TFEB and inducing lysosomal biogenesis in hepatocytes.

（Image by LI Xinjian's group）

Article link: https://doi.org/10.1016/j.devcel.2024.07.011

Contact: LI Xinjian

Institute of Biophysics, Chinese Academy of Sciences

Beijing 100101, China

E-mail: lixinjian@ibp.ac.cn

（Reported by Prof. LI Xinjian's group）