Checkpoint kinase 2 coordinates autophagy activation and Aurora kinase A degradation to regulate primary cilia for...

Checkpoint kinase 2 (CHEK2) is a tumor suppressor that safeguards genome integrity in the nucleus. It is also localized at the mother centriole. But the role of CHEK2 in this structure remains unclear. The primary cilium acts as a sensory organelle that regulates various aspects of cell behavior. However, the connection between CHEK2 and primary cilia has not been elucidated.

We investigated the role of CHEK2 in primary cilia regulation using both cultured cells and a zebrafish model. Pharmacological inhibition and genetic manipulation of CHEK2 were employed across systems, and rescue experiments were performed to validate the specificity of the findings. The primary cilia were observed using fluorescence or electron microscopy.

Here, we demonstrated that in response to nutrient deprivation, CHEK2 became activated to maintain primary cilia in both in vitro and in vivo loss-of-function and rescue studies. We found that CHEK2 maintained primary cilia by destabilizing Aurora Kinase A to prevent axoneme degradation and by activating AMPK to promote autophagy. Both pathways were essential for trophoblast ciliation, migration, and invasion. Moreover, in pancreatic ductal adenocarcinoma cells, glutamine deprivation activated CHEK2, which in turn coordinated autophagy induction and Aurora A degradation to sustain primary cilia and enhance invasive ability.

In summary, our study uncovers a novel role of CHEK2 in mediating cell invasion under metabolic stress by promoting autophagy and stabilizing axoneme to maintain primary cilia.