Cell contact and Nf2/Merlin-dependent regulation of TEAD palmitoylation and activity

Significance

The Hippo signaling pathway regulates cell proliferation in response to cell contact and a variety of other extracellular stimuli. It controls the activity and nuclear localization of cotranscriptional activator YAP, which interacts with DNA binding transcription factor TEAD, for the expression of target genes involved in cell proliferation. We show here that the expression level and transcriptional activity of TEAD are actively controlled by cell density through the modulation of its palmitoylation status. TEAD palmitoylation is controlled via fatty acid synthase and depalmitoylases in response to cell density. Our study indicates that the regulation of palmitoylation status is a potential target for controlling TEAD-dependent processes, perhaps including cancer growth.

Abstract

The Hippo pathway is involved in regulating contact inhibition of proliferation and organ size control and responds to various physical and biochemical stimuli. It is a kinase cascade that negatively regulates the activity of cotranscription factors YAP and TAZ, which interact with DNA binding transcription factors including TEAD and activate the expression of target genes. In this study, we show that the palmitoylation of TEAD, which controls the activity and stability of TEAD proteins, is actively regulated by cell density independent of Lats, the key kinase of the Hippo pathway. The expression of fatty acid synthase and acetyl-CoA carboxylase involved in de novo biosynthesis of palmitate is reduced by cell density in an Nf2/Merlin-dependent manner. Depalmitoylation of TEAD is mediated by depalmitoylases including APT2 and ABHD17A. Palmitoylation-deficient TEAD4 mutant is unstable and degraded by proteasome through the activity of the E3 ubiquitin ligase CHIP. These findings show that TEAD activity is tightly controlled through the regulation of palmitoylation and stability via the orchestration of FASN, depalmitoylases, and E3 ubiquitin ligase in response to cell contact.