The interconnected roles of spastin and protrudin in endosomal sorting

Endosomal tubule fission is associated with endoplasmic reticulum (ER)-endosome membrane contact sites and several ER proteins are required for efficient endosomal tubule fission. Our lab has previously identified two hereditary spastic paraplegia (HSP)- associated proteins, spastin (SPG4) and atlastin-1 (SPG3A), as essential for endosomal tubule fission. I investigated the functional interaction of spastin and protrudin and found that protrudin, an ER-associated adaptor molecule involved in anterograde membrane traffic, is a novel factor regulating endosomal tubule fission in non-polarised cells and in human iPSC-derived neurons. This required protrudin’s ability to bind VAPA/B and endosomal PtdIns3P, as well as its coiled coil domain previously implicated in kinesin-1 interaction. Tug-of-war between kinesin and dynein microtubule motors has been shown to be essential for endosomal tubule fission and I propose that protrudin functions in this process by promoting endosome interactions with kinesin-1, which generates anterograde pulling force on the endosome to counter-balance retrograde pulling force generated by dyneins. This work expands the repertoire of ER proteins involved in endosomal tubule fission and helps to understand how microtubule motors interact with other organelles to regulate membrane trafficking events. Considering protrudin is a potent enhancer of axon regeneration in the central nervous system, this might also help to elucidate the mechanisms underlying axonal health.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Kleniuk, Julia

Advisor dc:contributor.advisor

• Reid, Evan

• endosome
• neuron
• hereditary spastic paraplegia
• protrudin
• spastin

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/3040af0f-b991-4264-ac93-01542d8adf05/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.113678

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/376446