The membrane curvature-inducing REEP1-4 proteins generate an ER-derived vesicular compartment

Yoko Shibata (), Emily E. Mazur, Buyan Pan, Joao A. Paulo, Steven P. Gygi, Suyog Chavan, L. Sebastian Alexis Valerio, Jiuchun Zhang and Tom A. Rapoport ()
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Yoko Shibata: Harvard Medical School
Emily E. Mazur: Harvard Medical School
Buyan Pan: Harvard Medical School
Joao A. Paulo: Harvard Medical School
Steven P. Gygi: Harvard Medical School
Suyog Chavan: Harvard Medical School
L. Sebastian Alexis Valerio: Harvard Medical School
Jiuchun Zhang: Harvard Medical School
Tom A. Rapoport: Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract The endoplasmic reticulum (ER) is shaped by abundant membrane curvature-generating proteins that include the REEP family member REEP5. The REEP1 subfamily, consisting of four proteins in mammals (REEP1-4), is less abundant and lack a N-terminal region. Mutations in REEP1 and REEP2 cause Hereditary Spastic Paraplegia, but the function of these four REEP proteins remains enigmatic. Here we show that REEP1-4 reside in a unique vesicular compartment and identify features that determine their localization. Mutations in REEP1-4 that compromise curvature generation, including those causing disease, relocalize the proteins to the bulk ER. These mutants interact with wild-type proteins to retain them in the ER, consistent with their autosomal-dominant disease inheritance. REEP1 vesicles contain the membrane fusogen atlastin-1, but not general ER proteins. We propose that REEP1-4 generate these vesicles themselves by budding from the ER, and that they cycle back to the ER by atlastin-mediated fusion. The vesicles may serve to regulate ER tubule dynamics.

Date: 2024
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DOI: 10.1038/s41467-024-52901-6

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