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Updated: Jun 17, 2025

Isolation of Labile Multi-protein Complexes by in vivo Controlled Cellular Cross-Linking and Immuno-magnetic Affinity Chromatography
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Fatty links between multisystem proteinopathy and small VCP-interacting protein

Firyal Ramzan1, Ashish Kumar1, Fatima Abrar1

  • 1Department of Biology, University of Waterloo, Waterloo, ON, Canada.

Cell Death Discovery
|August 8, 2024
PubMed

Insights

Small VCP-interacting protein (SVIP) acylation is crucial for cell death in multisystem proteinopathy (MSP). Blocking SVIP myristoylation prevents cytotoxicity, suggesting SVIP acylation as a potential therapeutic target for MSP.

Area of Science:

  • Molecular biology
  • Genetics
  • Cellular biology

Background:

  • Multisystem proteinopathy (MSP) is a rare, dominantly inherited disorder caused by mutations in the valosin-containing protein (VCP) gene.
  • MSP encompasses frontotemporal dementia, inclusion body myopathy, Paget's disease of bone, and amyotrophic lateral sclerosis, with variable patient presentations.
  • VCP's diverse cellular functions are regulated by over 50 co-factors, including small VCP-interacting protein (SVIP).

Purpose of the Study:

  • To investigate the role of SVIP in VCP-mediated cellular dysfunction in MSP.
  • To determine if SVIP acylation influences VCP localization and cellular toxicity.

Main Methods:

  • Investigated SVIP's role in VCP localization to lysosomes.
  • Demonstrated SVIP myristoylation and palmitoylation.
  • Assessed the impact of SVIP acylation on cell death in the presence of a VCP variant.

Main Results:

  • SVIP directs VCP to lysosomes in an acylation-dependent manner.
  • SVIP undergoes myristoylation at Glycine 2 and palmitoylation at Cysteines 4 and 7.
  • SVIP acylation is required for cell death induced by the MSP-associated R155H-VCP variant; blocking myristoylation prevents this toxicity.

Conclusions:

  • SVIP acylation is a critical mediator of VCP-associated cytotoxicity in MSP.
  • Targeting SVIP acylation, particularly myristoylation, may offer a novel therapeutic strategy for MSP.

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