3 years ago

Regulation of the Hippo-YAP Pathway by Glucose Sensor O-GlcNAcylation

Regulation of the Hippo-YAP Pathway by Glucose Sensor O-GlcNAcylation
The Hippo pathway is crucial in organ size control and tissue homeostasis, with deregulation leading to cancer. An extracellular nutrition signal, such as glucose, regulates the Hippo pathway activation. However, the mechanisms are still not clear. Here, we found that the Hippo pathway is directly regulated by the hexosamine biosynthesis pathway (HBP) in response to metabolic nutrients. Mechanistically, the core component of Hippo pathway (YAP) is O-GlcNAcylated by O-GlcNAc transferase (OGT) at serine 109. YAP O-GlcNAcylation disrupts its interaction with upstream kinase LATS1, prevents its phosphorylation, and activates its transcriptional activity. And this activation is not dependent on AMPK. We also identified OGT as a YAP-regulated gene that forms a feedback loop. Finally, we confirmed that glucose-induced YAP O-GlcNAcylation and activation promoted tumorigenesis. Together, our data establish a molecular mechanism and functional significance of the HBP in directly linking extracellular glucose signal to the Hippo-YAP pathway and tumorigenesis.

Graphical abstract

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Teaser

Peng et al. report that YAP is O-GlcNAcylated by OGT at serine 109. YAP O-GlcNAcylation disrupts its interaction with the upstream kinase LATS1, preventing its phosphorylation and activating its transcriptional activity, therefore promoting tumorigenesis.

Publisher URL: www.sciencedirect.com/science

DOI: S1097276517307591

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