The direct interaction with transcriptional factor TEAD4 implied a straightforward regulation mechanism of tumor suppressor NF2

As an output effecter of Hippo signaling pathway, the transcription factor TEAD and co-activator YAP play crucial functions in promoting cell proliferation and organ size. The tumor suppressor NF2 has been shown to activate LATS1/2 kinases and interplay with Hippo pathway to suppress YAP-TEAD complex. But, whether and how NF2 could directly regulate TEAD remains unknown. We identified a direct link and physical interaction between NF2 and TEAD4. NF2 interacted with TEAD4 through its FERM domain and the C-terminal tail, and decreased protein stability of TEAD4 independently of LATS1/2 and YAP. Furthermore, NF2 inhibited TEAD4 palmitoylation and retained the cytoplasmic translocation of TEAD4, resulting in ubiquitination and dysfunction of TEAD4. Moreover, the interaction with TEAD4 is required for NF2 function to suppress cell proliferation. These findings revealed a new role of NF2 as a binding partner and inhibitor of the transcription factor TEAD, and would shed light on an alternative mechanism of how NF2 functions as a tumor suppressor through the Hippo signaling cascade.