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

Cogo, S; Tomkins, JE; Vavouraki, N; Giusti, V; Forcellato, F; Franchin, C; Tessari, I; Arrigoni, G; Cendron, L; Manzoni, C; Civiero, L; Lewis, PA; Greggio, E

doi:10.1016/j.nbd.2022.105858

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

Cogo, S; Tomkins, JE; Vavouraki, N; Giusti, V; Forcellato, F; Franchin, C; Tessari, I; Arrigoni, G; Cendron, L; Manzoni, C; Civiero, L; Lewis, PA; Greggio, E

Authors

S Cogo

JE Tomkins

N Vavouraki

V Giusti

F Forcellato

C Franchin

I Tessari

G Arrigoni

L Cendron

C Manzoni

L Civiero

PA Lewis

E Greggio

Abstract

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 physiopathological roles with mechanistic dissection of its associated pathways.

Citation

Cogo, S., Tomkins, J., Vavouraki, N., Giusti, V., Forcellato, F., Franchin, C., …Greggio, E. (2022). Cytosolic sequestration of spatacsin by Protein Kinase A and 14-3-3 proteins. Neurobiology of Disease, 174, https://doi.org/10.1016/j.nbd.2022.105858

Journal Article Type	Article
Acceptance Date	Sep 8, 2022
Online Publication Date	Sep 9, 2022
Publication Date	2022
Deposit Date	Aug 15, 2023
Publicly Available Date	Aug 15, 2023
Print ISSN	0969-9961
Publisher	Elsevier
Peer Reviewed	Peer Reviewed
Volume	174
DOI	https://doi.org/10.1016/j.nbd.2022.105858
Keywords	Hereditary spastic paraplegia (HSP); SPG11; Spatacsin; Protein -protein interactions (PPI); 14-3-3s; Protein Kinase A (PKA); Intracellular trafficking; SPASTIC PARAPLEGIA; SPG11; PHOSPHORYLATION; MUTATIONS; LOCALIZATION; PREDICTION; UNIVERSAL; MEMBRANE; M