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Abstract:
Arginine/lysine-rich motifs typically function as targeting signals for the
translocation of proteins to the nucleus. Here, we demonstrate that such a
motif consisting of four basic amino acids in the polyglutamine protein
ataxin-3 (Atx-3) serves as a recognition site for the interaction with the
molecular chaperone VCP. Through this interaction, VCP modulates the
fibrillogenesis of pathogenic forms of Atx-3 in a concentration-dependent
manner, with low concentrations of VCP stimulating fibrillogenesis and excess
concentrations suppressing it. No such effect was observed with a mutant Atx-3
variant, which does not contain a functional VCP interaction motif. Strikingly,
a stretch of four basic amino acids in the ubiquitin chain assembly factor E4B
was also discovered to be critical for VCP binding, indicating that
arginine/lysine-rich motifs might be generally utilized by VCP for the
targeting of proteins. In vivo studies with Drosophila models confirmed that
VCP selectively modulates aggregation and neurotoxicity induced by pathogenic
Atx-3. Together, these results define the VCP–Atx-3 association as a potential
target for therapeutic intervention and suggest that it might influence the
progression of spinocerebellar ataxia type 3.
