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

Cogo, S. ORCID: https://orcid.org/0000-0002-5792-6897, Tomkins, J. E., Vavouraki, N., Giusti, V., Forcellato, F., Franchin, C., Tessari, I., Arrigoni, G., Cendron, L., Manzoni, C., Civiero, L., Lewis, P. A. and Greggio, E. (2022) Cytosolic sequestration of spatacsin by Protein Kinase A and 14-3-3 proteins. Neurobiology of Disease, 174. 105858. ISSN 1095-953x

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To link to this item DOI: 10.1016/j.nbd.2022.105858

Abstract/Summary

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

Item Type:Article
Refereed:Yes
Divisions:Life Sciences > School of Biological Sciences > Biomedical Sciences
Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
ID Code:107439
Publisher:Elsevier

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