Receptor oligomerization guides pathway choice between proteasomal and autophagic degradation

Area of Science:

• Cellular Biology
• Molecular Biology
• Neuroscience

Background:

• Misfolded and aggregated proteins are cytotoxic, leading to neurodegenerative diseases like Alzheimer's and Parkinson's.
• Cellular protein quality control pathways, including the proteasome and selective autophagy, degrade or eliminate abnormal proteins.
• The precise mechanisms governing the choice between these degradation pathways remain incompletely understood.

Purpose of the Study:

• To investigate the molecular mechanisms determining pathway choice between proteasomal degradation and selective autophagy for abnormal protein clearance.
• To elucidate the role of ubiquitin receptors and their binding modules in directing substrates to specific degradation pathways.

Main Methods:

• Utilized yeast models to study protein degradation pathways.
• Employed modular artificial receptors with varying ubiquitin-binding and oligomerization potentials.
• Analyzed substrate ubiquitylation and receptor interactions.

Main Results:

• Pathway choice is determined after substrate ubiquitylation by competing ubiquitin receptors.
• Autophagy receptors prevail over proteasome receptors when substrates aggregate and receptors bundle.
• Receptor oligomerization potential, rather than ubiquitin-binding affinity, is the primary determinant of pathway selection.

Conclusions:

• Proteasomal degradation and selective autophagy function as branches of an adaptive protein quality control system.
• Substrate ubiquitylation serves as a common signal initiating degradation via either pathway.
• Receptor properties, particularly oligomerization, dictate the specific route for protein clearance.