Jane Jardine, Marine Tarrillon, Gwennan André-Grégoire, Kilian Trillet, Vanessa Josso, Laura Merlet, Rosalie Moreau, Célia Jaunasse, Luc Antigny, Séverine Marionneau-Lambot, François Guillonneau, Alice Boissard, Cécile Henry, Joanna Re, Sophie Barillé-Nion, Nadine Laguette, Philippe P Juin, Julie Gavard, Nicolas Bidère
The cGAS-STING pathway is an evolutionarily conserved DNA-sensing mechanism that triggers innate immune responses. cGAS and STING play dual roles in tumorigenesis, promoting antitumor immunity and cell death while fueling tumor growth and metastasis. However, the mechanisms fine-tuning this pathway remain elusive. Using complementary proteomic approaches, we report that Casein Kinase 1 alpha (CK1α) operates as a bimodal regulator of the cGAS-STING pathway. CK1α supports optimal DNA sensing by counteracting proteasome-dependent degradation of cGAS, which involves the Cullin-RING ubiquitin ligase 3 (CRL3). Conversely, CK1α restrains signal propagation in response to STING agonists, tempering IRF3 activation. Exploiting these counterposing functions, we show that selective degradation of CK1α using molecular-glue degraders suppressed aberrant cGAS-STING-driven inflammation signaling in a chromosomally unstable triple-negative breast cancer cell line, while cooperating with a STING agonist to promote apoptosis in acute myeloid leukemia cells. Thus, CK1α's dual regulatory role in the cGAS-STING pathway presents a promising target for therapeutic development.