ER\xa0\u2013\xa0lysosome contacts at a pre-axonal region regulate axonal lysosome availability

Nazmiye Özkan,Ginny G Farías,Casper C Hoogenraad,Nalan Liv,Daphne Jurriens,Inge Van Soest,Lukas C Kapitein,Alexandra Van Harten,Judith Klumperman,Max Koppers

doi:10.1038/s41467-021-24713-5

Nazmiye Özkan, Ginny G Farías + Show 8 more

Open Access

https://doi.org/10.1038/s41467-021-24713-5

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Abstract

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.

Highlights

Neuronal function relies on careful coordination of organelle organization and transport
We find that endoplasmic reticulum (ER) tubule – late endosomes (LEs)/lysosome contacts are enriched in a pre-axonal region
ER tubules are generated by two main ER tubule-shaping proteins, RTN4 and DP1, while flattened ER cisternae are maintained by CLIMP63

Summary

Introduction

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. It is unclear how organelle organization, inter-organelle communication and transport are linked and how this contributes to local organelle availability in neurons. 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. Lysosomes have been visualized in both unpolarized cells and in neurons from brain tissue[8,12], it is less clear how ER remodeling regulates these organelle interactions

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