Cell Reports
Volume 23, Issue 7, 15 May 2018, Pages 2026-2038
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Article
Sensory-Neuropathy-Causing Mutations in ATL3 Cause Aberrant ER Membrane Tethering

https://doi.org/10.1016/j.celrep.2018.04.071Get rights and content
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Highlights

  • HSAN-causing ATL3 mutants are less fusogenic but retain their dimerization capacity

  • Recombinant mutant ATL3 proteins cause excessive liposome tethering

  • In cells, HSAN-causing ATL3 mutants lead to collapse of the ER

  • Volume EM revealed that ER collapse is hallmarked by laterally tethered ER tubules

Summary

The endoplasmic reticulum (ER) is a complex network of sheets and tubules that is continuously remodeled. The relevance of this membrane dynamics is underscored by the fact that mutations in atlastins (ATLs), the ER fusion proteins in mammals, cause neurodegeneration. How defects in this process disrupt neuronal homeostasis is unclear. Using electron microscopy (EM) volume reconstruction of transfected cells, neurons, and patient fibroblasts, we show that hereditary sensory and autonomic neuropathy (HSAN)-causing ATL3 mutants promote aberrant ER tethering hallmarked by bundles of laterally attached ER tubules. In vitro, these mutants cause excessive liposome tethering, recapitulating the results in cells. Moreover, ATL3 variants retain their dimerization-dependent GTPase activity but are unable to promote membrane fusion, suggesting a defect in an intermediate step of the ATL3 functional cycle. Our data show that the effects of ATL3 mutations on ER network organization go beyond a loss of fusion and shed light on neuropathies caused by atlastin defects.

Keywords

peripheral neuropathy
HSAN
atlastin
ER
membrane fusion
membrane tethering
FIB-SEM
GTPase

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These authors contributed equally

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