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

Dependence receptors (DRs) induce cell death by apoptosis in the absence of their ligand. Among them, Kremen1 was first described to induce cancer cell death in the absence of its ligand, DKK1. Nevertheless, the exact mechanism of Kremen1-triggered cell death remains unexplored. In this study, we demonstrate that Kremen1 induces cell death with autophagic features, contrasting with the apoptotic process typically associated with dependence receptors. Specifically, chemical inhibition of autophagy by spautin or wortmannin or genetic inhibition of ATG9A or ATG18B effectively blocks this cell death process. Furthermore, through a proximity protein interactome analysis of Kremen1, we identified Sec24C, a component of the COP-II complex, as important effector of Kremen1-induced autophagy and cell death. Our findings reveal an interaction between Sec24C and ATG8 regulated by Kremen1, potentially underlying the increased number of autophagosomes in cancer cells, leading to their death. This correlation between Kremen1 and the induction of aberrant autophagy deserves particular attention, especially as the Kremen1/DKK1 pair is frequently altered in cancers, with higher DKK1 expression associated with poor survival outcomes. Thus, targeting this pathway may offer a potential strategy for treating cancers resistant to current therapies.