Clearance of bacteria by macrophages involves internalization of the microorganisms into phagosomes, which are then delivered to endolysosomes for enzymatic degradation. These spatiotemporally segregated processes are not known to be functionally coupled. Here, we show that lysosomal degradation of bacteria sustains phagocytic uptake. In Drosophila and mammalian macrophages, lysosomal dysfunction due to loss of the endolysosomal Cl⁻ transporter ClC-b/CLCN7 delayed degradation of internalized bacteria. Unexpectedly, defective lysosomal degradation of bacteria also attenuated further phagocytosis, resulting in elevated bacterial load. Exogenous application of bacterial peptidoglycans restored phagocytic uptake in the lysosomal degradation-defective mutants via a pathway requiring cytosolic pattern recognition receptors and NF-κB. Mammalian macrophages that are unable to degrade internalized bacteria also exhibit compromised NF-κB activation. Our findings reveal a role for phagolysosomal degradation in activating an evolutionarily conserved signaling cascade, which ensures that continuous uptake of bacteria is preceded by lysosomal degradation of microbes.

通过巨噬细胞清除细菌涉及将微生物内化为吞噬体，然后将其递送至溶酶体进行酶促降解。这些时空分离的过程在功能上是未知的。在这里，我们表明细菌的溶酶体降解维持吞噬细胞摄取。在果蝇和哺乳动物巨噬细胞溶酶体功能障碍是由于内溶酶体氯的损失^-转运蛋白ClC-b / CLCN7延迟了内在细菌的降解。出乎意料的是，细菌的溶酶体降解缺陷也减弱了进一步的吞噬作用，导致细菌载量升高。细菌肽聚糖的外源应用通过需要胞质模式识别受体和NF-κB的途径恢复了溶酶体降解缺陷型突变体的吞噬摄取。不能降解内在细菌的哺乳动物巨噬细胞也表现出受损的NF-κB活化。我们的发现揭示了吞噬酶体降解在激活进化上保守的信号级联反应中的作用，从而确保细菌的持续吸收先于微生物的溶酶体降解。