Allison et al. reveal how a protein linked to hereditary spastic paraplegia (HSP) promotes the traffic of endosomal tubules that recycle proteins back to the cell surface.
Mutations in the gene encoding the microtubule-severing protein spastin cause a dominant form of HSP. Spastin helps remodel membranes at the ER, where it interacts with several proteins that shape membrane tubules, and at the midbody, where it promotes cytokinesis. Spastin also localizes to endosomes, but its function at this organelle is unknown. In wild-type cells, plasma membrane proteins are recycled to the cell surface in membrane tubules that pinch off from sorting endosomes, leaving behind proteins that, after being internalized into vesicles inside the endosome lumen, are transported to lysosomes to be degraded.
Allison et al. found that, in the absence of spastin, recycling tubules failed to separate from sorting endosomes, prompting cargo such as the transferrin receptor to be degraded instead of returned to the plasma membrane. Tubule fission wasn’t restored by spastin mutants unable to sever microtubules or by versions of the protein unable to bind IST1, a component of the ESCRT-III complex that sorts endosomal cargo into intralumenal vesicles. Cells lacking IST1 showed similar defects in tubule fission and transferrin receptor trafficking, suggesting that IST1 recruits spastin to coordinate the recycling and degradation of endosomal proteins.
Defects in this process may give rise to HSP. Knocking down spastin or IST1 inhibited the growth of zebrafish motor axons. The endosomes in these neurons were abnormally tubulated, which could, says senior author Evan Reid, affect the trafficking of signaling proteins like the BMP receptor that are crucial for axon development.
Text by Ben Short