Fatty links between multisystem proteinopathy and Small VCP-Interacting Protein

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.31.531359v1?rss=1 Authors: Ramzan, F., Abrar, F., Kumar, A., Liao, L. M. Q., Campbell, Z. E., Gray, R. V., Akanni, O., Guyn, C. M., Martin, D. D. O. Abstract: Multi-system 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 these 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 autophagosomes in an acylation-dependent manner. We demonstrate that SVIP is myristoylated at glycine 2 and palmitoylated at cysteines 4 and 7. Acylation of SVIP was required to mediate cell death in the presence of the MSP- associated VCP variant (R155H-VCP), whereby blocking SVIP myristoylation rescues cytotoxicity. Therefore, SVIP acylation may present a novel target in MSP. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC