The pathogenic mutant vimentin L387P disrupts endoplasmic reticulum organization and proteostasis

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Abstract The organization and dynamic regulation of the vimentin intermediate filament network are essential for diverse cellular processes, including cell division, cytoskeletal crosstalk, and organelle positioning. In particular, the vimentin network is required to maintain a compact perinuclear endoplasmic reticulum (ER) that supports the ER quality-control compartment. Here, we show that the vimentin variant c.1160T>C (L387P), identified in a progeroid syndrome, disrupts ER organization and function. In SW13/cl.2 cells, vimentin L387P forms aggregates containing cisternal-like structures of predominant perinuclear localization that associate with pronounced nuclear distortion. These aggregates sequester chaperones, the SEL1L/HRD1 complex, and the 20S proteasomal subunit, while excluding RNF26 and VCP/p97. This extensive redistribution of ER-associated degradation components coincides with impaired proteostasis and reduced free Ca 2+ in intra-organelle compartments, indicating compromised ER functionality. Altogether, these findings suggest that the L387P mutation drives extensive ER disorganization and highlight the importance of an intact vimentin network for ER homeostasis.

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