Cytosolic sequestration of spatacsin by Protein Kinase A and 14-3-3 proteins

• DOI: 10.1016/j.nbd.2022.105858
• Publication Date: 2022-09-09T17:20:31Z
• Authors: Susanna Cogo; James E. Tomkins; Nikoleta Vavouraki; Veronica Giusti; Federica Forcellato; Cinzia Franchin; Isabella Tessari; Giorgio Arrigoni; Laura Cendron; Claudia Manzoni; Laura Civiero; Patrick A. Lewis; Elisa Greggio
• Keywords: Hereditary Spastic Paraplegia; Transport protein

Mutations in SPG11, encoding spatacsin, constitute the major cause of autosomal recessive Hereditary Spastic Paraplegia (HSP) with thinning corpus callosum. Previous studies showed that spatacsin orchestrates cellular traffic events through formation a coat-like complex and its loss function results lysosomal axonal transport impairments. However, upstream mechanisms regulate trafficking are unknown. Here, using proteomics CRISPR/Cas9-mediated tagging endogenous we identified subset 14-3-3 proteins as physiological interactors spatacsin. The interaction is modulated by Protein Kinase A (PKA)-dependent phosphorylation at Ser1955, which initiates from plasma membrane to intracellular space. Our study provides novel insight understanding physio-pathological roles mechanistic dissection associated pathways.