title: Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates.
abstract: The two main routes that cells use for degrading intracellular proteins are the ubiquitin-proteasome and autophagy-lysosome pathways, which have been thought to have largely distinct clients. Here, we show that autophagy inhibition increases levels of proteasome substrates. This is largely due to p62 (also called A170/SQSTM1) accumulation after autophagy inhibition. Excess p62 inhibits the clearance of ubiquitinated proteins destined for proteasomal degradation by delaying their delivery to the proteasome's proteases. Our data show that autophagy inhibition, which was previously believed to only affect long-lived proteins, will also compromise the ubiquitin-proteasome system. This will lead to increased levels of short-lived regulatory proteins, like p53, as well as the accumulation of aggregation-prone proteins, with predicted deleterious consequences.
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Viktor I
authors.initials: VI
authors.lastname: Korolchuk
authors.forename: Alicia
authors.initials: A
authors.lastname: Mansilla
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Menzies
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex