OTUD6A orchestrates complex modulation of TEAD4-mediated transcriptional programs

Area of Science:

• Molecular Biology
• Cell Signaling
• Gene Regulation

Background:

• TEAD transcription factors are key regulators in the Hippo signaling pathway.
• Understanding the regulation of TEAD factors is crucial for deciphering cellular processes and disease mechanisms.

Purpose of the Study:

• To investigate the regulatory role of OTU domain-containing protein 6A (OTUD6A) on the transcriptional enhancer factor TEAD4 (TEAD4).
• To elucidate the molecular mechanisms by which OTUD6A influences YAP-TEAD-mediated transcription.

Main Methods:

• Co-immunoprecipitation assays to identify protein interactions.
• Structural analyses to determine interaction domains.
• Functional assays (e.g., reporter assays) to assess transcriptional activity.
• Western blotting to evaluate protein stability and localization.

Main Results:

• OTUD6A was identified as a deubiquitinase that interacts with TEAD4.
• OTUD6A positively regulates TEAD-driven transcription without affecting TEAD4 stability.
• Specific interaction domains were mapped to the N-terminal domain of OTUD6A and the YAP-binding domain of TEAD4.
• OTUD6A enhances YAP-TEAD4 complex formation, suppresses VGLL4-TEAD4 interaction, and promotes YAP-TEAD4 binding to target gene promoters.
• OTUD6A modulates nuclear interactions but does not alter TEAD4 nuclear localization.

Conclusions:

• OTUD6A acts as a positive regulator of TEAD4 transcriptional activity through specific protein-protein interactions.
• The findings reveal a novel regulatory mechanism of YAP-TEAD complexes by a deubiquitinase.
• This study provides valuable insights into the pathogenesis of diseases associated with dysregulated YAP-TEAD signaling.