An integrated stress response-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation

The Integrated Stress Response (ISR) is a corrective physiological program to restore cellular homeostasis that is based on the attenuation of global protein synthesis and a resource-enhancing transcriptional programme. GCN2 is the oldest of four kinases that are activated by diverse cellular stresses to trigger the ISR and acts as the primary responder to amino acid shortage and ribosome collisions. Here, using a broad multi-omic approach, we uncover an ISR-independent role of GCN2. GCN2 inhibition or depletion in the absence of discernible stress causes excessive protein synthesis and ribosome biogenesis, perturbs the cellular translatome, and results in a dynamic and broad loss of metabolic homeostasis. Cancer cells that rely on GCN2 to keep protein synthesis in check under conditions of full nutrient availability depend on GCN2 for survival and unrestricted tumour growth. Our observations define an ISR-independent role of GCN2 in regulating the cellular proteome and translatome and suggest new avenues for cancer therapies based on unleashing excessive mRNA translation.