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

• Published in: Nature communications Vol. 15; no. 1; pp. 8655 - 16
• Main Authors: Shibata, Yoko, Mazur, Emily E., Pan, Buyan, Paulo, Joao A., Gygi, Steven P., Chavan, Suyog, Valerio, L. Sebastian Alexis, Zhang, Jiuchun, Rapoport, Tom A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 14/19; 14/28; 631/80; 631/80/313; 631/80/642/1463; 82/58; 82/83; Animals; Curvature; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; GTP Phosphohydrolases; GTP-Binding Proteins; HEK293 Cells; HeLa Cells; Hereditary spastic paraplegia; Humanities and Social Sciences; Humans; Localization; Membrane fusion; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Membranes; Mice; multidisciplinary; Mutation; Paraplegics; Proteins; Science; Science (multidisciplinary); Spastic Paraplegia, Hereditary - genetics; Spastic Paraplegia, Hereditary - metabolism; Vesicle fusion; Vesicles
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52901-6

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. REEP domain-containing proteins generate membrane curvature, and some are known to shape the endoplasmic reticulum (ER). Here, the authors show that four understudied members, REEPs 1-4, localize to vesicles that appear to bud out of, and fuse back with, ER.