Molecular mechanism of HUWE1-HAPSTR1-USP7-mediated ubiquitin chain amplification on nuclear proteins.

HUWE1-HAPSTR1-USP7 complex amplifies ubiquitin chains on nuclear proteins, regulating stress-responsive degradation with a key role in neurodevelopmental disorders and cancer.

• Why it matters: Understanding how HUWE1 selectively targets short-lived proteins is crucial for insights into cellular stress responses and disease mechanisms, yet this process remains poorly understood.
• What they did: The study used structural, biochemical, and proteomic analyses to investigate the complex, revealing that HUWE1 functions as a ubiquitin chain amplifier regulated by HAPSTR1 and USP7, with a cryo-EM structure elucidating their interactions.
• The result: This work shows that the complex drives extensive nuclear proteome remodeling, providing a molecular basis for HUWE1's role in disease and highlighting it as a potential therapeutic target.