Polyglutamine tracts regulate autophagy
Taylor & Francis
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Rubinsztein, D., Ashkenazi, A., Bento, C., Ricketts, T., Vicinanza, M., Siddiqi, F., Pavel, M., et al. (2017). Polyglutamine tracts regulate autophagy. Autophagy, 13 (9), 1613-1614. https://doi.org/10.1080/15548627.2017.1336278
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.
We are grateful to Wellcome Trust (Principal Research Fellowship to DCR.) (095317/Z/11/Z), Wellcome Trust Strategic Grant to Cambridge Institute for Medical Research (100140/Z/12/Z)), National Institute for Health Research Biomedical Research Center at Addenbrooke's Hospital, Addenbrooke's Charitable Trust and Federation of European Biochemical Societies (FEBS Long-Term Fellowship to A.A.) for funding.
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (095317/Z/11/Z)
External DOI: https://doi.org/10.1080/15548627.2017.1336278
This record's URL: https://www.repository.cam.ac.uk/handle/1810/266042