PUBLICATION
An initial HOPS-mediated fusion event is critical for autophagosome transport initiation from the axon terminal
- Authors
- Wisner, S.R., Chlebowski, M., Mandal, A., Mai, D., Stein, C., Petralia, R.S., Wang, Y.X., Drerup, C.M.
- ID
- ZDB-PUB-240620-38
- Date
- 2024
- Source
- Autophagy 20(10): 2275-2296 (Journal)
- Registered Authors
- Chlebowski, Mady, Drerup, Katie (Catherine)
- Keywords
- Axon terminal, Vps18, autophagy, axonal transport, lysosome, neuron
- MeSH Terms
-
- Animals
- Autophagosomes*/metabolism
- Autophagy*/physiology
- Axons*/metabolism
- Biological Transport
- Endosomes/metabolism
- Humans
- Lysosomes/metabolism
- Membrane Fusion/physiology
- Neurons/metabolism
- Vesicular Transport Proteins*/genetics
- Vesicular Transport Proteins*/metabolism
- Zebrafish*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 38899385 Full text @ Autophagy
Citation
Wisner, S.R., Chlebowski, M., Mandal, A., Mai, D., Stein, C., Petralia, R.S., Wang, Y.X., Drerup, C.M. (2024) An initial HOPS-mediated fusion event is critical for autophagosome transport initiation from the axon terminal. Autophagy. 20(10):2275-2296.
Abstract
In neurons, macroautophagy/autophagy is a frequent and critical process. In the axon, autophagy begins in the axon terminal, where most nascent autophagosomes form. After formation, autophagosomes must initiate transport to exit the axon terminal and move toward the cell body via retrograde transport. During retrograde transport these autophagosomes mature through repetitive fusion events. Complete lysosomal cargo degradation occurs largely in the cell body. The precipitating events to stimulate retrograde autophagosome transport have been debated but their importance is clear: disrupting neuronal autophagy or autophagosome transport is detrimental to neuronal health and function. We have identified the HOPS complex as essential for early autophagosome maturation and consequent initiation of retrograde transport from the axon terminal. In yeast and mammalian cells, HOPS controls fusion between autophagosomes and late endosomes with lysosomes. Using zebrafish strains with loss-of-function mutations in vps18 and vps41, core components of the HOPS complex, we found that disruption of HOPS eliminates autophagosome maturation and disrupts retrograde autophagosome transport initiation from the axon terminal. We confirmed this phenotype was due to loss of HOPS complex formation using an endogenous deletion of the HOPS binding domain in Vps18. Finally, using pharmacological inhibition of lysosomal proteases, we show that initiation of autophagosome retrograde transport requires autophagosome maturation. Together, our data demonstrate that HOPS-mediated fusion events are critical for retrograde autophagosome transport initiation through promoting autophagosome maturation. This reveals critical roles for the HOPS complex in neuronal autophagy which deepens our understanding of the cellular pathology of HOPS-complex linked neurodegenerative diseases.Abbreviations: CORVET: Class C core vacuole/endosome tethering; gRNA: guide RNA; HOPS: homotypic fusion and protein sorting; pLL: posterior lateral line; Vps18: VPS18 core subunit of CORVET and HOPS complexes; Vps41: VPS41 subunit of HOPS complex.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping