Ku70 senses cytosolic DNA and assembles a tumor-suppressive signalosome
Menée in vitro et à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel la protéine Ku70, en se liant à l'ADN cytosolique et en formant un complexe protéique avec la GTPase Ras et la kinase Raf, réduit la prolifération des cellules cancéreuses et supprime la tumorigenèse
The innate immune response contributes to the development or attenuation of acute and chronic diseases, including cancer. Microbial DNA and mislocalized DNA from damaged host cells can activate different host responses that shape disease outcomes. Here, we show that mice and humans lacking a single allele of the DNA repair protein Ku70 had increased susceptibility to the development of intestinal cancer. Mechanistically, Ku70 translocates from the nucleus into the cytoplasm where it binds to cytosolic DNA and interacts with the GTPase Ras and the kinase Raf, forming a tripartite protein complex and docking at Rab5+Rab7+ early-late endosomes. This Ku70-Ras-Raf signalosome activates the MEK-ERK pathways, leading to impaired activation of cell cycle proteins Cdc25A and CDK1, reducing cell proliferation and tumorigenesis. We also identified the domains of Ku70, Ras, and Raf involved in activating the Ku70 signaling pathway. Therapeutics targeting components of the Ku70 signalosome could improve the treatment outcomes in cancer. Ku70 undergoes cytoplasmic translocation in response to DNA and forms a signalosome to attenuate the development of cancer.