Fatty links between multisystem proteinopathy and small VCP-interacting protein.

Autor: Ramzan F; Department of Biology, University of Waterloo, Waterloo, ON, Canada., Kumar A; Department of Biology, University of Waterloo, Waterloo, ON, Canada., Abrar F; Department of Biology, University of Waterloo, Waterloo, ON, Canada., Gray RAV; Department of Biology, University of Waterloo, Waterloo, ON, Canada., Campbell ZE; Department of Biology, University of Waterloo, Waterloo, ON, Canada., Liao LMQ; Department of Biology, University of Waterloo, Waterloo, ON, Canada., Dang A; Department of Biology, University of Waterloo, Waterloo, ON, Canada., Akanni O; Department of Biology, University of Waterloo, Waterloo, ON, Canada., Guyn C; Department of Biology, University of Waterloo, Waterloo, ON, Canada., Martin DDO; Department of Biology, University of Waterloo, Waterloo, ON, Canada. dale.martin@uwaterloo.ca.
Jazyk: angličtina
Zdroj: Cell death discovery [Cell Death Discov] 2024 Aug 08; Vol. 10 (1), pp. 358. Date of Electronic Publication: 2024 Aug 08.
DOI: 10.1038/s41420-024-02118-9
Abstrakt: Multisystem proteinopathy (MSP) is a rare, dominantly inherited disorder that includes a cluster of diseases, including frontotemporal dementia, inclusion body myopathy, and Paget's disease of bone. MSP is caused by mutations in the gene encoding valosin-containing protein (VCP). Patients with the same mutation, even within the same family, can present with a different combination of any or all of the above diseases, along with amyotrophic lateral sclerosis (ALS). The pleiotropic effects may be linked to the greater than 50 VCP co-factors that direct VCP's many roles in the cell. Small VCP-interacting protein (SVIP) is a small protein that directs VCP to autophagosomes and lysosomes. We found that SVIP directs VCP localization to lysosomes in an acylation-dependent manner. We demonstrate that SVIP is myristoylated at Glycine 2 and palmitoylated at Cysteines 4 and 7. Acylation of SVIP is required to mediate cell death in the presence of the MSP-associated VCP variant (R155H-VCP), whereas blocking SVIP myristoylation prevents cytotoxicity. Therefore, SVIP acylation may present a novel target in MSP.
(© 2024. The Author(s).)
Databáze: MEDLINE
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