Kremen1 dependence receptor induces SEC24C and ATG9A-dependent cell death.

Among dependence receptors (DRs), which induce apoptosis when unbound by their cognate ligands, Kremen1 was initially reported to drive cancer cell death in the absence of DKK1. However, the precise mechanism of Kremen1-induced cell death remains unclear. In this study, we demonstrate that Kremen1 induces cell death with autophagic features, contrasting with the apoptotic process typically associated with DRs. Functional experiments using pharmacological inhibition of autophagy or genetic silencing of key autophagy effectors, confirmed this cell death process. Protein–protein proximity assays through biotin labeling identified SEC24C, a component of the COP-II complex, as a critical effector of this process. Moreover, the proximity between Kremen1, SEC24C and ATG9A after vesicular trafficking, fosters the proximity of SEC24C with ATG8, ERGIC and ATG9A, likely increasing the number of autophagosomes and vesicles leading to cell death. Given that the Kremen1/DKK1 pair is frequently altered in cancers, its aberrant induction should be monitored and may be targeted to offer an alternative strategy to treat cancers resistant to current therapies.