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PreprintCited by 8Cellular transport and secretionCholesterol and Lipid MetabolismLipid Membrane Structure and Behavior

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ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway

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Veronese, Matteo, Kallabis, Sebastian, Kaczmarek, Alexander Tobias, Das, Anushka, Robers, Lennart, Schumacher, Simon, Lofrano, Alessia, Brodesser, Susanne, Müller, Stefan, Hofmann, Kay, Krüger, Marcus, Rugarli, Elena I.·2024·Life Science Alliance
DOI 10.1101/2024.01.17.576039PMC PMC11116810

Preprint — published as 10.26508/lsa.202402620 · Paper page

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Abstract

Complexes of ERLIN1 and ERLIN2 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 and RNF170. We identify a luminal N-terminal conserved region in TMUB1 and RNF170 required for this interaction. Three-dimensional modelling shows that this conserved motif binds the SPFH domain of two adjacent ERLIN subunits at different interfaces. Protein variants that preclude these interactions have been previously linked to hereditary spastic paraplegia (HSP). By using omics approaches in combination with phenotypic characterisation of cells lacking both ERLINs, we demonstrate a role for ERLIN scaffolds in maintaining cholesterol levels in the ER by favouring transport to the Golgi over esterification, thereby regulating Golgi morphology and the secretory pathway.

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Metadata

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
openRxiv
Published
2024-01-18
Volume
7
Issue
8
Pages
e202402620-e202402620
ISSN
2575-1077 (ISSN-L)
DOI
10.1101/2024.01.17.576039
PMC
PMC11116810
OpenAlex
W4398248913
Cited by
8
References
1
Citations by year
2026: 3 · 2025: 3 · 2024: 2
FWCI
1.79
Type
journal article
Language
en
Open access
Licence
cc-by
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)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › 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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