PKA-mediated phosphorylation of SPG11/spatacsin regulates binding with a subset of 14-3-3 proteins

Mutations in SPG11 constitute the major cause of autosomal recessive Hereditary Spastic Paraplegia (HSP) with thinning of the corpus callosum. Previous studies showed that SPG11/spatacsin orchestrates cellular traffic events through the formation of a coat-like complex and its loss of function results in lysosomal impairments. However, the upstream mechanisms that regulate SPG11/spatacsin trafficking are unknown. Here, using proteomics and CRISPR/Cas9-mediated tagging of endogenous SPG11/spatacsin, we identified a subset of 14-3-3 proteins as physiological interactors of SPG11. The interaction is modulated by PKA-dependent phosphorylation of SPG11 at Ser1955, which initiates SPG11 trafficking from the plasma membrane. Our study provides novel insight in understanding SPG11 physio-pathological roles with mechanistic dissection of its associated pathways. ### Competing Interest Statement The authors have declared no competing interest.