Lysosomal damage sensing and lysophagy initiation by SPG20-ITCH.

Area of Science:

• Cell Biology
• Molecular Biology
• Neuroscience

Background:

• Cells possess mechanisms to repair damaged lysosomes or initiate lysophagy (lysosomal autophagy).
• The precise decision-making process governing lysosomal damage response remains incompletely understood.

Purpose of the Study:

• To elucidate the molecular pathway that distinguishes between lysosomal membrane repair and lysophagy.
• To identify key proteins and mechanisms involved in detecting lysosomal damage and initiating lysophagy.

Main Methods:

• Investigated protein interactions on damaged lysosomes using human cell models.
• Utilized techniques to detect lipid bilayer perturbations and protein recruitment.
• Analyzed the role of SPG20, IST1, and ITCH in the lysosomal damage response pathway.

Main Results:

• Identified SPG20 as a sensor of lipid-packing defects in compromised lysosomal membranes.
• Demonstrated that SPG20 integrates damage detection with recruitment of the repair factor IST1.
• Showed that extensive damage triggers SPG20 to recruit and activate ITCH, leading to ubiquitin-63-linked chain formation and lysophagy initiation.
• Linked SPG20 to the triage of damaged lysosomes for destruction.

Conclusions:

• Uncovered a novel pathway for detecting and responding to lysosomal membrane damage.
• This pathway involves SPG20 sensing lipid defects and coordinating with IST1 and ITCH to initiate lysophagy.
• Findings highlight the importance of a coordinated lysosomal damage response for cellular homeostasis and have implications for neurodegenerative diseases linked to SPG20.