Polyglutamine tracts regulate autophagy

Abstract

Expansions of polyglutamine (polyQ) tracts in different proteins cause 9 neurodegenerative conditions, such as Huntington disease and various ataxias. However, many normal mammalian proteins contain shorter polyQ tracts. As these are frequently conserved in multiple species, it is likely that some of these polyQ tracts have important but unknown biological functions. Here we review our recent study showing that the polyQ domain of the deubiquitinase ATXN3/ataxin-3 enables its interaction with BECN1/beclin 1, a key macroautophagy/autophagy initiator. ATXN3 regulates autophagy by deubiquitinating BECN1 and protecting it from proteasomal degradation. Interestingly, expanded polyQ tracts in other polyglutamine disease proteins compete with the shorter ATXN3 polyQ stretch and interfere with the ATXN3-BECN1 interaction. This competition results in decreased BECN1 levels and impaired starvation-induced autophagy, which phenocopies the loss of autophagic function mediated by ATXN3. Our findings describe a new autophagy-protective mechanism that may be altered in multiple neurodegenerative diseases.

Keywords: Beclin 1; Huntington's disease; ataxin-3; autophagy; polyglutamine; spinocerebellar ataxia.

Figure 1.

A proposed model describing ATXN3 activity in autophagy and its downregulation by mutant polyQ disease proteins. (A) The polyQ domain in wild-type ATXN3 (WT-Q) interacts with the evolutionarily conserved domain (ECD) of BECN1. This interaction allows the deubiquitinase activity of ATXN3 to protect BECN1 from degradation by the proteasome and thus enables autophagy. (B) Some expanded polyQ proteins (µ-QQQ) can compete in trans with the shorter polyQ stretch in wild-type ATXN3 for BECN1 binding. This competition destabilizes BECN1. (C) Expansion of the polyQ domain in ATXN3 decreases the deubiquitinase (DUB) activity toward BECN1 and enhances the interaction of mutant ATXN3 with BECN1. This would outcompete wild-type ATXN3 binding to BECN1 and destabilizes BECN1.