Protein folding state-dependent sorting at the Golgi apparatus.

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Organelle-specific protein quality control (PQC) is vital for eukaryotic cellular homeostasis.
• The Golgi apparatus's role in PQC has been largely unexplored despite its function in protein processing.
• Understanding Golgi-mediated PQC is essential for cellular health and disease research.

Purpose of the Study:

• To investigate the mechanisms by which the Golgi apparatus contributes to protein quality control.
• To identify how unfolded or misfolded proteins are handled within the Golgi.
• To elucidate the sorting and trafficking pathways for aberrant proteins in the secretory pathway.

Main Methods:

• Utilized chemical biology-based protein unfolding systems to probe protein behavior in the Golgi.
• Analyzed the segregation of unfolded proteins from correctly folded proteins.
• Tracked the export of quality control substrates in distinct vesicular carriers.

Main Results:

• Demonstrated segregation of unfolded proteins from folded proteins within the Golgi apparatus.
• Identified distinct carriers for exporting unfolded proteins and aggregated cargo.
• Showed that oligomerized proteins are targeted for lysosomal degradation, while unfolded proteins return to the ER for refolding.
• Revealed checkpoints for Golgi export and lysosomal targeting of QC substrates.

Conclusions:

• The Golgi apparatus acts as a critical checkpoint for protein quality control, sorting misfolded proteins for degradation or refolding.
• The observed ER localization of misfolded proteins in disease mutants may arise from distinct mechanisms.
• This study provides new insights into the cellular machinery maintaining proteostasis within the secretory pathway.