ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway
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Abstract
Complexes of ERLIN1 and ERLIN2 (ER lipid raft–associated 1 and 2) form large ring-like cup-shaped structures on the endoplasmic reticulum (ER) membrane and serve as platforms to bind cholesterol and E3 ubiquitin ligases, potentially defining functional nanodomains. Here, we show that ERLIN scaffolds mediate the interaction between the full-length isoform of TMUB1 (transmembrane and ubiquitin-like domain–containing 1) and RNF170 (RING finger protein 170). We identify a luminal N-terminal conserved region in TMUB1 and RNF170, which is required for this interaction. Three-dimensional modelling shows that this conserved motif binds the stomatin/prohibitin/flotillin/HflKC domain of two adjacent ERLIN subunits at different interfaces. Protein variants that preclude these interactions have been previously linked to hereditary spastic paraplegia. Using omics-based approaches in combination with phenotypic characterization of HeLa cells lacking both ERLINs, we demonstrate a role of ERLIN scaffolds in limiting cholesterol esterification, thereby favouring cholesterol transport from the ER to the Golgi apparatus and regulating Golgi morphology and the secretory pathway.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Lu, J. P., Wang, Y., Sliter, D. A., Pearce, M. M. P., & Wojcikiewicz, R. J. H. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.251983 · Cited by 102 · cited 3× · see citing works
“ERLINs have been found in association with the autocrine motility factor receptor (AMFR) (Jo et al, 2011), RNF170 (Pearce et al, 2007; Lu et al, 2011), RNF185 (Fenech et al, 2020; van de Weijer et al, 2020), and RNF5 (Fenech et al, 2020), although the exact organization of these complexes has not…”
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- Authors
- Veronese, M., Kallabis, S., Kaczmarek, A. T., Das, A., Robers, L., Schumacher, S., Lofrano, A., Brodesser, S., Müller, S., Hofmann, K., Krüger, M., & Rugarli, E. I.
- Affiliations
- University of Cologne (DE)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Corresponding author
- Rugarli, Elena I
- ORCID
- Venue
- Life Science Alliance
- Publisher
- Life Science Alliance, LLC
- Published
- 2024-05-23
- Volume
- 7
- Issue
- 8
- Pages
- e202402620
- ISSN
- 2575-1077 (ISSN-L)
- PMC
- PMC11116810
- OpenAlex
- W4398248913
- Cited by
- 8
- References
- 2
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Life Science Alliance (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Deutsche Forschungsgemeinschaft (RU 1653/4-1, 411422114)
- Walter and Monika Neupert Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Keywords
- ERLIN2, cholesterol esterification, endoplasmic reticulum, Golgi apparatus, secretory pathway, protein-protein interaction, E3 ubiquitin ligase, hereditary spastic paraplegia, cholesterol transport, nanodomains, Golgi morphology
- MeSH terms
- Cholesterol, Endoplasmic Reticulum, Golgi Apparatus, HeLa Cells, Humans, Membrane Proteins, Nerve Tissue Proteins, Protein Binding, Ubiquitin-Protein Ligases, Secretory Pathway
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