CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
Department of Cell Physiology and Metabolism, University of Geneva, Geneva 1211, Switzerland.
Cell Host Microbe. 2018 Jun 13;23(6):766-774.e5. doi: 10.1016/j.chom.2018.04.013. Epub 2018 May 17.
Macrophages represent the first line of immune defense against pathogens, and phagosome acidification is a necessary step in pathogen clearance. Here, we identified the bicarbonate transporter SLC4A7, which is strongly induced upon macrophage differentiation, as critical for phagosome acidification. Loss of SLC4A7 reduced acidification of phagocytosed beads or bacteria and impaired the intracellular microbicidal capacity in human macrophage cell lines. The phenotype was rescued by wild-type SLC4A7, but not by SLC4A7 mutants, affecting transport capacity or cell surface localization. Loss of SLC4A7 resulted in increased cytoplasmic acidification during phagocytosis, suggesting that SLC4A7-mediated, bicarbonate-driven maintenance of cytoplasmic pH is necessary for phagosome acidification. Altogether, we identify SLC4A7 and bicarbonate-driven cytoplasmic pH homeostasis as an important element of phagocytosis and the associated microbicidal functions in macrophages.
巨噬细胞是抵御病原体的第一道免疫防线，而吞噬体酸化是清除病原体的必要步骤。在这里，我们鉴定出碳酸氢盐转运蛋白 SLC4A7，它在巨噬细胞分化时被强烈诱导，对于吞噬体酸化至关重要。SLC4A7 的缺失降低了吞噬的珠子或细菌的酸化，并损害了人巨噬细胞系中的细胞内杀菌能力。野生型 SLC4A7 可挽救表型，但不能挽救影响转运能力或细胞表面定位的 SLC4A7 突变体。SLC4A7 的缺失导致吞噬过程中细胞质酸化增加，表明 SLC4A7 介导的、碳酸氢盐驱动的细胞质 pH 稳态对于吞噬体酸化是必要的。总的来说，我们确定 SLC4A7 和碳酸氢盐驱动的细胞质 pH 稳态是吞噬作用以及巨噬细胞中相关杀菌功能的一个重要组成部分。
