ER - lysosome contacts at a pre-axonal region regulate axonal lysosome availability

Neuronal function relies on careful coordination of organelle organization and transport. Kinesin-1 mediates transport of the endoplasmic reticulum (ER) and lysosomes into the axon and it is increasingly recognized that contacts between the ER and lysosomes influence organelle organization. However, it is unclear how organelle organization, inter-organelle communication and transport are linked and how this contributes to local organelle availability in neurons. Here, we show that somatic ER tubules are required for proper lysosome transport into the axon. Somatic ER tubule disruption causes accumulation of enlarged and less motile lysosomes at the soma. ER tubules regulate lysosome size and axonal translocation by promoting lysosome homo-fission. ER tubule - lysosome contacts often occur at a somatic pre-axonal region, where the kinesin-1-binding ER-protein P180 binds microtubules to promote kinesin-1-powered lysosome fission and subsequent axonal translocation. We propose that ER tubule - lysosome contacts at a pre-axonal region finely orchestrate axonal lysosome availability for proper neuronal function. In neurons and other cells, contacts between organelles regulates function and subcellular organization, but the precise mechanisms and effects are unclear. Here the authors show that endoplasmic reticulum (ER) tubules in the soma of neurons regulate lysosome localization and function by regulating lysosomal fission, suggesting a role for ER - lysosome inter-organelle membrane contact sites in lysosomal axonal availability.

Automated summary

This study demonstrates the role of endoplasmic reticulum (ER) tubules in regulating lysosome localization and function in neurons, by promoting lysosomal fission. These findings suggest that ER - lysosome inter-organelle membrane contact sites play a crucial role in determining lysosomal availability in axons.