TAK1 inhibition activates pore-forming proteins to block intracellular bacterial growth through modulating mitochondria

Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), known as TAK1, is a central mediator of intracellular host defense signaling promoting inflammatory gene expression. Hence, TAK1 is a prime target of intracellular bacterial effectors in blocking inflammatory responses. However, when TAK1 is inhibited, host cells alternatively activate multiple cell death pathways, namely caspase 8-dependent apoptosis and pyroptosis, and receptor interacting protein kinase 3 (RIPK3)-dependent necroptosis. While these pathways ultimately lead to cell death, we found that they also modulate mitochondria to produce mitochondrial reactive oxygen species (ROS). Although as cell death executors, mixed lineage kinase-like (MLKL) and gasdermins are known to form pores in the plasma membrane, we found that TAK1 inhibition translocates them to mitochondria resulting in elevated mitochondrial ROS. Ablation of both MLKL and gasdermins diminished TAK1 inhibition-induced elevation of ROS and exacerbated intracellular bacterial colonization. Our results reveal that these cell death pathways have an alternative host defense role to prevent intracellular pathogen colonization.