STING engages PKR to drive lysosomal cell death in lung ischemia-reperfusion injury.

Stimulator of interferon genes (STING) has been implicated in multiple forms of cell death. However, the effector kinases that couple STING to these death programs remain poorly defined. Here, we show that during lung ischemia-reperfusion injury, mitochondrial DNA release engages the cyclic GMP-AMP synthase (cGAS)-STING pathway to trigger lysosomal cell death (LCD) in mouse and rat models. In human lung epithelial cells, STING oligomerization at the endoplasmic reticulum drives autophosphorylation of double-stranded RNA-dependent protein kinase (PKR) at serine 33. This phosphorylation of PKR activates IκB kinase-NF-κB signaling independently of the canonical STING-TBK1 and PKR-eIF2α pathways. In turn, NF-κB induces LAMP3 transcription, promoting lysosomal membrane permeabilization and LCD. STING-PKR signaling is also observed in patient-derived lung epithelial cells and alveolar organoids. These findings identify PKR as a non-canonical STING effector and show that blockade of STING-PKR signaling attenuates epithelial LCD and lung injury.