The ER membrane protein complex restricts mitophagy by controlling BNIP3 turnover

Area of Science:

• Cell Biology
• Molecular Biology
• Autophagy Research

Background:

• Selective autophagy, including mitophagy, is typically assessed by lysosomal degradation of autophagy receptors.
• Mitophagy receptors like BNIP3 and BNIP3L/NIX are crucial for targeting mitochondria for degradation.
• Understanding the precise mechanisms regulating these receptors is key to understanding selective autophagy.

Purpose of the Study:

• To investigate the lysosomal degradation pathway of mitophagy receptors BNIP3 and BNIP3L/NIX.
• To identify novel factors involved in the trafficking and degradation of BNIP3.
• To elucidate the interplay between different cellular degradation systems in regulating BNIP3 homeostasis.

Main Methods:

• Genome-wide CRISPR screen to identify factors affecting BNIP3 flux.
• Analysis of autophagy-independent lysosomal delivery pathways.
• Investigating the roles of endolysosomal and ubiquitin-proteasome systems in BNIP3 regulation.

Main Results:

• BNIP3 and BNIP3L/NIX are constitutively delivered to lysosomes independently of autophagy.
• Endolysosomal components, including the ER membrane protein complex (EMC), are critical for BNIP3 lysosomal trafficking.
• The endolysosomal and ubiquitin-proteasome systems regulate BNIP3 independently, and perturbing either affects mitophagy and cellular physiology.

Conclusions:

• Lysosomal degradation of BNIP3 occurs via an autophagy-independent, endosomal pathway.
• Endosomal trafficking and lysosomal degradation are key regulators of tail-anchored protein localization.
• These findings expand the understanding of tail-anchored protein quality control and selective autophagy mechanisms.