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

Veronese, M.; Kallabis, S.; Kaczmarek, A.; Robers, L.; Schumacher, S.; Das, A.; Lofrano, A.; Brodesser, S.; Müller, S.; Hofmann, K.; Krüger, M.; Rugarli, E. I.

doi:10.1101/2024.01.17.576039

bioRxiv · 10.1101/2024.01.17.576039

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

Veronese, M.·Kallabis, S.·Kaczmarek, A.·Robers, L.·Schumacher, S.·Das, A.·Lofrano, A.·Brodesser, S.·Müller, S.·Hofmann, K.·Krüger, M.·Rugarli, E. I.

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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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Veronese, M., Kallabis, S., Kaczmarek, A., Robers, L., Schumacher, S., Das, A., Lofrano, A., Brodesser, S., Müller, S., Hofmann, K., Krüger, M., Rugarli, E. I.. 2024-01-18. ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway. https://doi.org/10.1101/2024.01.17.576039

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