14-3-3 Binding to Ataxin-1(ATXN1) Regulates Its Dephosphorylation at Ser-776 and Transport to the Nucleus

Abstract

Background: Phosphorylation at Ser-776 of the polyglutamine disease-associated protein Ataxin-1 modulates its function.Results: 14-3-3 binding stabilizes Ataxin-1 by blocking dephosphorylation of pS776 and impedes Ataxin-1 transport to the nucleus.Conclusion: 14-3-3 must disassociate from Ataxin-1 for its transport to the nucleus.Significance: 14-3-3 regulates Ataxin-1 function by protecting phosphorylation of Ser-776 and Ataxin-1 entry into the nucleus.

Beyond the Glutamine Expansion: Influence of Posttranslational Modifications of Ataxin-1 in the Pathogenesis of Spinocerebellar Ataxia Type 1

“…The primary outcome of this interaction is the stabilization of ATXN1 proteins. The binding of 14-3-3 to ATXN1 prevents the dephosphorylation of pS776 and protects ATXN1 from subsequent proteolysis [20]. The phosphorylation-mimetic ATXN1 (ATXN1-D776) is unable to bind 14-3-3, but is as stable as pS776-ATXN1 [18, 20].…”

“…The binding of 14-3-3 to ATXN1 prevents the dephosphorylation of pS776 and protects ATXN1 from subsequent proteolysis [20]. The phosphorylation-mimetic ATXN1 (ATXN1-D776) is unable to bind 14-3-3, but is as stable as pS776-ATXN1 [18, 20]. This suggests that 14-3-3 may stabilize ATXN1 indirectly by protecting the phosphorylation at S776, rather than by the direct physical interaction itself.…”

“…1). Thus, the interaction of 14-3-3 proteins with ATXN1 may prevent ATXN1 from entering the nucleus by masking the nuclear localization signal [20]. The overexpression of 14-3-3 is shown to increase the toxicity of the polyglutamine-expanded ATXN1 in Drosophila [15].…”

“…Protein phosphatase 2A (PP2A) was identified as a potential ATXN1-pS776 phosphatase in the cerebellum by a glutathione S-transferase (GST) pull-down assay [20]. PP2A dephosphorylates ATXN1-pS776 and knock-down of PP2A expression increases the amount of ATXN1-pS776 in transfected cells in vitro .…”

“…Collectively, these data support the hypothesis that PP2A is a phosphatase for pS776 in ATXN1 in the mouse cerebellum. Dephosphorylation of ATXN1 at S776 is restricted to the nucleus of cerebellar cells [20]. This compartmentalization can be explained by the fact that ATXN1-pS776 interacts with14-3-3 proteins in the cytoplasm, blocking dephosphorylation of pS776 by PP2A.…”