Glutamine synthetase modulates YAP activation by stabilizing LATS under glutamine homeostasis

Glutamine homeostasis plays a crucial role in fundamental cellular processes and is often dysregulated in cancer cells; however, the underlying mechanisms governing this homeostasis remain unclear. Here, we demonstrate that enriched glutamine activates the Hippo pathway. Mechanistically, glutamine synthetase (GS) interacts with LATS1, leading to its downregulation via increased ubiquitin degradation. Glutamine supplementation reduces the expression of GS and stabilizes LATS1, leading to YAP phosphorylation and inhibition. Clinically, GS expression is associated with clinical outcomes and inversely correlated with LATS1 expression and YAP1 phosphorylation. Taken together, these results not only uncover a previously undescribed mechanism by which glutamine homeostasis regulates the Hippo pathway but also suggest a potential therapeutic strategy by targeting glutamine metabolism and key growth-related signaling pathways for cancer treatment.