Fig. 7

Schematic representation of the proposed interplay between ataxin-3 and OGT in protein clearance. (A) Under physiological conditions, wild-type ataxin-3 (Atx3wt) serves as a DUB to OGT, partly rescuing the latter from proteasomal degradation and thereby indirectly lowering autophagic flux (20). This counteracts the positive autophagy regulation by ataxin-3 (64). The equilibrium between positive and negative feedback of wild-type ataxin-3 toward autophagy allows a proper degradation of misfolded proteins and compromised organelles in a healthy cellular context. (B) In MJD, polyQ-expanded ataxin-3 (Atx3ex) presents enhanced DUB activity toward OGT, which culminates in reduced degradation and thus increased OGT protein levels. This process leads to a further suppression and impairment of autophagy by preventing autophagosome–lysosome fusion (20), ultimately resulting in accumulation of toxic soluble and aggregated forms of polyQ-expanded ataxin-3.