TY - JOUR
T1 - Polyglutamine tracts regulate autophagy
AU - Ashkenazi, Avraham
AU - Bento, Carla F.
AU - Ricketts, Thomas
AU - Vicinanza, Mariella
AU - Siddiqi, Farah
AU - Pavel, Mariana
AU - Squitieri, Ferdinando
AU - Hardenberg, Maarten C.
AU - Imarisio, Sara
AU - Menzies, Fiona M.
AU - Rubinsztein, David C.
PY - 2017/9/2
Y1 - 2017/9/2
N2 - 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.
AB - 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.
KW - ataxin-3
KW - autophagy
KW - Beclin 1
KW - Huntington's disease
KW - polyglutamine
KW - spinocerebellar ataxia
UR - http://www.scopus.com/inward/record.url?scp=85026374061&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85026374061&partnerID=8YFLogxK
U2 - 10.1080/15548627.2017.1336278
DO - 10.1080/15548627.2017.1336278
M3 - Comment/debate
AN - SCOPUS:85026374061
VL - 13
SP - 1613
EP - 1614
JO - Autophagy
JF - Autophagy
SN - 1554-8627
IS - 9
ER -