Dredd-mediated cleavage of Kenny uncouples the IKK complex from selective autophagy to enable innate immunity

Selective autophagy restrains innate immune signalling to maintain tissue homeostasis, yet how this repression is rapidly relieved during infection remains unclear. Here, we show that under basal conditions the inhibitor of {kappa}B kinase {gamma} (IKK{gamma}) Kenny is sequestered at autophagosomes through Atg8 and the selective autophagy receptor Ref(2)P, thereby silencing Imd pathway activity. Bacterial infection disrupts this interaction, releasing the IKK complex to enable immune signalling. Mechanistically, we identify the initiator caspase Dredd as a direct interactor of the IKK{gamma} Kenny and show that Dredd binds and cleaves Kenny in a ubiquitination-dependent manner during infection. This cleavage removes an N-terminal LC3-interacting region, uncoupling the IKK complex from autophagosomal degradation. Dredd-mediated processing of Kenny stabilises the IKK complex and is required for activation of the NF-{kappa}B transcription factor Relish, robust antibacterial responses, and host survival following infection. Together, these findings uncover a mechanism by which caspase-mediated cleavage intersects with selective autophagy to dynamically control NF-{kappa}B signalling during bacterial infection. Short summaryBacterial infection activates NF-{kappa}B signalling by triggering caspase-dependent cleavage of the IKK subunit Kenny, releasing the IKK complex from autophagosomal repression to enable effective innate immune responses.