Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt

Area of Science:

• Cell Biology
• Developmental Biology
• Molecular Biology

Background:

• Wingless (Wg)/Wnt signaling pathways are crucial for development and cellular functions.
• Cellular responsiveness to Wg/Wnt ligands depends on both ligand concentration and target cell sensitivity.
• The Wg/Wnt receptor Frizzled plays a key role in mediating these signals.

Purpose of the Study:

• To investigate the role of ubiquitylation and deubiquitylation in regulating Wg/Wnt receptor Frizzled.
• To identify the mechanisms controlling Frizzled cell surface levels and Wg/Wnt signaling responsiveness.
• To explore the function of deubiquitylating enzymes in Wg/Wnt pathway regulation.

Main Methods:

• Utilized mammalian cell culture and Drosophila models.
• Investigated the ubiquitylation and deubiquitylation status of Frizzled.
• Assessed the impact of UBPY/USP8 on Frizzled trafficking, cell surface levels, and Wg/Wnt signaling.
• Analyzed lysosomal degradation and plasma membrane recycling pathways.

Main Results:

• A balance between ubiquitylation and deubiquitylation of Frizzled dictates cellular responsiveness to Wg/Wnt.
• Deubiquitylating enzyme UBPY/ubiquitin-specific protease 8 (USP8) regulates cell surface Frizzled levels.
• UBPY/USP8-dependent deubiquitylation promotes Frizzled recycling to the plasma membrane, counteracting lysosomal degradation.
• Modulating UBPY/USP8 activity directly impacts the strength of canonical Wg/Wnt signaling.

Conclusions:

• The study reveals a novel mechanism controlling Wg/Wnt signaling responsiveness through the regulation of Frizzled cell surface levels.
• Ubiquitylation and deubiquitylation of Frizzled, mediated by UBPY/USP8, are critical determinants of pathway activity.
• This regulatory axis provides a new target for understanding and potentially manipulating Wg/Wnt signaling in biological processes.