Mammalian Intracellular Dickkopf1 Couples Proteostasis with Inflammation

Inflammation and cellular stress mutually regulate each other and are hallmarks of various diseases. The mechanistic basis of this interaction remains incompletely understood. Here, we report that proteostatic stress triggers the transcription and intracellular accumulation of Dickkopf1 (DKK1) in a p38-dependent fashion. Intracellular DKK1 sustains the high inflammatory tone in inherently stressed cells and is required for mounting cytokine responses following ligation of toll-like and cytokine receptors. Leveraging unbiased proteomics and bioinformatic analysis, we identify a physical interaction between intracellular DKK1 and Copine1 (CPNE1), which promotes NFκB-dependent inflammation irrespective of upstream phosphorylation checkpoints and IκBα degradation. Genetic deletion of DKK1, but not pharmacological neutralization of secreted DKK1, ameliorates inflammation and organ damage in a mouse model of sepsis. Collectively, we identify DKK1 as a target of the cellular stress response and uncover a non-canonical, cell-intrinsic function of DKK1 in the control of NFκB-mediated inflammation, thus providing novel insights into the coupling of homeostatic perturbations and immunity.