Dissection of Molecular Mechanisms in Lysophagy Tamotsu Yoshimori Graduate School of Frontier Biosciences/Graduate School of Medicine, Osaka University, Japan
Autophagy is a tightly regulated intracellular degradation system that plays fundamental roles in cellular homeostasis. While starvation-induced autophagy is a non-selective process, there are also selective autophagy specifically targeting bacteria, aggregate-prone proteins, damaged mitochondria and so on. We recently identified that autophagy also selectively sequesters damaged lysosomes. This “lysophagy” maintains lysosomal homeostasis and suppresses development of nephropathy in hyperuricemic mice.
These damaged lysosomes are ubiquitinated first then autophagic machinery is recruited via recognizing ubiquitin, which form autophagosomes around the membrane. To dissect the underlying mechanisms in lysophagy including the molecule recognizing the damage of lysosomes, we performed proteomics analysis on the damaged membrane. Here we identified the E3 ligase complex that is involving at the initial stage of lysophagy. Upon damage, the complex is recruited to lysosomes through binding of the receptor subunit to one of major lysosomal membrane proteins. Finally, the complex ubiquitinates it and others, which is essential to lysophagy.
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