Fatty links between multisystem proteinopathy and small VCP-interacting protein

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.