Mito-xenophagic killing of bacteria is coordinated by a metabolic switch in dendritic cells

Radomski, Nadine GND; Kägebein, Danny GND; Liebler-Tenorio, Elisabeth M. GND; Karger, Axel GND; Rufer, Elke GND; Tews, Birke Andrea GND; Nagel, S.; Einenkel, Rebekka; Müller, A.; Rebbig, Annica; Knittler, Michael R. GND

Chlamydiae are bacterial pathogens that grow in vacuolar inclusions. Dendritic cells (DCs) disintegrate these compartments, thereby eliminating the microbes, through auto/xenophagy, which also promotes chlamydial antigen presentation via MHC I. Here, we show that TNF-α controls this pathway by driving cytosolic phospholipase (cPLA)2-mediated arachidonic acid (AA) production. AA then impairs mitochondrial function, which disturbs the development and integrity of these energy-dependent parasitic inclusions, while a simultaneous metabolic switch towards aerobic glycolysis promotes DC survival. Tubulin deacetylase/autophagy regulator HDAC6 associates with disintegrated inclusions, thereby further disrupting their subcellular localisation and stability. Bacterial remnants are decorated with defective mitochondria, mito-aggresomal structures, and components of the ubiquitin/autophagy machinery before they are degraded via mito-xenophagy. The mechanism depends on cytoprotective HSP25/27, the E3 ubiquitin ligase Parkin and HDAC6 and promotes chlamydial antigen generation for presentation on MHC I. We propose that this novel mito-xenophagic pathway linking innate and adaptive immunity is critical for effective DC-mediated anti-bacterial resistance.



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Radomski, Nadine / Kägebein, Danny / Liebler-Tenorio, Elisabeth / et al: Mito-xenophagic killing of bacteria is coordinated by a metabolic switch in dendritic cells. 2017.


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