Portioning organelles for autophagic clearance.

Area of Science:

• Cell Biology
• Molecular Biology
• Autophagy Research

Background:

• Organellophagy, the selective autophagy of organelles, is crucial for cellular homeostasis and quality control.
• Autophagy receptors mediate organellophagy by linking organelles to the autophagic machinery via LC3 proteins.
• These receptors are activated by various cellular stresses, initiating organelle clearance.

Purpose of the Study:

• To investigate the structural and functional role of intrinsically disordered regions (IDRs) in organellophagy receptors.
• To determine the mechanism by which organellophagy receptors induce organelle fragmentation.
• To explore the therapeutic potential of manipulating organellophagy.

Main Methods:

• Analysis of mammalian and yeast organellophagy receptors, focusing on LIRs within IDRs.
• Experimental manipulation of IDR modules to assess their role in organelle fragmentation.
• Investigating the role of LC3 engagement in lysosomal delivery.

Main Results:

• All known organellophagy receptors utilize LIRs embedded within intrinsically disordered regions (IDRs).
• IDR modules are interchangeable and sufficient to induce organelle fragmentation independently of LC3.
• LC3 engagement is specifically required for lysosomal delivery of fragmented organelles.

Conclusions:

• Intrinsically disordered regions of organellophagy receptors are critical for initiating organelle fragmentation.
• Organelle fragmentation by IDRs is separable from LC3-dependent lysosomal targeting.
• ORGAnelle TArgeting Chimeras (ORGATACs) offer a novel therapeutic strategy for controlled organelle fragmentation and clearance.