A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy

Area of Science:

• Cellular Biology
• Molecular Biology
• Biochemistry

Background:

• Protein quality control is vital for cellular health, and its failure leads to misfolded protein accumulation.
• Aggrephagy, a selective form of autophagy, is a key pathway for clearing protein aggregates.
• Dysfunctional protein aggregate clearance is linked to various diseases, including neurodegenerative disorders.

Purpose of the Study:

• To investigate the mechanism of aggregate fragmentation prior to autophagic clearance.
• To identify the molecular players involved in aggregate fragmentation and compaction.
• To explore the role of these players in the context of disease-associated protein inclusions.

Main Methods:

• Utilized biochemical assays and cellular imaging techniques.
• Investigated the function of the 19S proteasomal regulatory particle and the DNAJB6-HSP70-HSP110 chaperone module.
• Examined the impact on the formation of huntingtin inclusions.

Main Results:

• Fragmentation is a prerequisite for the autophagic clearance of amorphous protein aggregates.
• The 19S proteasomal regulatory particle and the DNAJB6-HSP70-HSP110 chaperone module are essential for aggregate fragmentation and compaction.
• These molecular components facilitate the clustering of autophagy receptors, initiating aggregate removal.
• The identified players also delay the formation of disease-associated huntingtin inclusions.

Conclusions:

• Aggrephagy is a piecemeal process involving aggregate fragmentation before clearance.
• The 19S proteasomal regulatory particle and DNAJB6-HSP70-HSP110 module have novel roles in aggrephagy.
• These findings offer insights into the mechanisms underlying proteinopathies and potential therapeutic targets.