Life science alliance · 2025
An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Román-Trufero Mónica, Kleijn Istvan T, Blighe Kevin, Zhou Jinglin, Saavedra-García Paula, Gaffar Abigail, Christoforou Marilena, Bellotti Axel, Abrahams Joel, Atrih Abdelmadjid, Lamont Douglas, Gierlinski Marek, Jayaprakash Pooja, Michel Audrey M, Aboagye Eric O, Yuneva Mariia, Masson Glenn R, Shahrezaei Vahid, Auner Holger W
Аннотация
The integrated stress response (ISR) is a corrective physiological programme 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-omics 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 describe 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.