Successful elimination of bacteria in phagocytes occurs in the phago-lysosomal system, but also depends on mitochondrial pathways. Yet, how these two organelle systems communicate is largely unknown. Here we identify the lysosomal biogenesis factor transcription factor EB (TFEB) as regulator for phago-lysosome-mitochondria crosstalk in macrophages. By combining cellular imaging and metabolic profiling, we find that TFEB activation, in response to bacterial stimuli, promotes the transcription of aconitate decarboxylase (Acod1, Irg1) and synthesis of its product itaconate, a mitochondrial metabolite with antimicrobial activity. Activation of the TFEB–Irg1–itaconate signalling axis reduces the survival of the intravacuolar pathogen Salmonella enterica serovar Typhimurium. TFEB-driven itaconate is subsequently transferred via the Irg1-Rab32–BLOC3 system into the Salmonella-containing vacuole, thereby exposing the pathogen to elevated itaconate levels. By activating itaconate production, TFEB selectively restricts proliferating Salmonella, a bacterial subpopulation that normally escapes macrophage control, which contrasts TFEB’s role in autophagy-mediated pathogen degradation. Together, our data define a TFEB-driven metabolic pathway between phago-lysosomes and mitochondria that restrains Salmonella Typhimurium burden in macrophages in vitro and in vivo.

吞噬细胞中细菌的成功消除发生在吞噬溶酶体系统中，但也取决于线粒体途径。然而，这两个细胞器系统如何通信在很大程度上是未知的。在这里，我们确定溶酶体生物发生因子转录因子 EB (TFEB) 作为巨噬细胞中吞噬-溶酶体-线粒体串扰的调节剂。通过结合细胞成像和代谢分析，我们发现 TFEB 激活，响应细菌刺激，促进乌头酸脱羧酶 (Acod1, Irg1) 的转录和其产物衣康酸的合成，这是一种具有抗菌活性的线粒体代谢物。TFEB-Irg1-衣康酸信号轴的激活降低了液泡内病原体沙门氏菌的存活率鼠伤寒血清型。TFEB 驱动的衣康酸随后通过 Irg1-Rab32-BLOC3 系统转移到含沙门氏菌的液泡中，从而使病原体暴露于升高的衣康酸水平。通过激活衣康酸的产生，TFEB 选择性地限制增殖的沙门氏菌，这是一种通常逃避巨噬细胞控制的细菌亚群，这与 TFEB 在自噬介导的病原体降解中的作用形成鲜明对比。总之，我们的数据定义了吞噬溶酶体和线粒体之间的 TFEB 驱动的代谢途径，该途径在体外和体内抑制巨噬细胞中鼠伤寒沙门氏菌的负担。