title: Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy.
abstract: A major function of proteasomes and macroautophagy is to eliminate misfolded potentially toxic proteins. Mammalian proteasomes, however, cannot cleave polyglutamine (polyQ) sequences and seem to release polyQ-rich peptides. Puromycin-sensitive aminopeptidase (PSA) is the only cytosolic enzyme able to digest polyQ sequences. We tested whether PSA can protect against accumulation of polyQ fragments. In cultured cells, Drosophila and mouse muscles, PSA inhibition or knockdown increased aggregate content and toxicity of polyQ-expanded huntingtin exon 1. Conversely, PSA overexpression decreased aggregate content and toxicity. PSA inhibition also increased the levels of polyQ-expanded ataxin-3 as well as mutant α-synuclein and superoxide dismutase 1. These protective effects result from an unexpected ability of PSA to enhance macroautophagy. PSA overexpression increased, and PSA knockdown or inhibition reduced microtubule-associated protein 1 light chain 3-II (LC3-II) levels and the amount of protein degradation sensitive to inhibitors of lysosomal function and autophagy. Thus, by promoting autophagic protein clearance, PSA helps protect against accumulation of aggregation-prone proteins and proteotoxicity.
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Menzies
authors.forename: Raphael
authors.initials: R
authors.lastname: Hourez
authors.forename: Sara
authors.initials: S
authors.lastname: Imarisio
authors.forename: Marcel
authors.initials: M
authors.lastname: Raspe
authors.forename: Oana
authors.initials: O
authors.lastname: Sadiq
authors.forename: Dhia
authors.initials: D
authors.lastname: Chandraratna
authors.forename: Cahir
authors.initials: C
authors.lastname: O'Kane
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Rock
authors.forename: Eric
authors.initials: E
authors.lastname: Reits
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Goldberg
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000067699:Ataxin-3; D001343:Autophagy; D002460:Cell Line; D004330:Drosophila; D055785:Gene Knockdown Techniques; D006801:Humans; D000071058:Huntingtin Protein; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010455:Peptides; D012097:Repressor Proteins; C000606290:SOD1 protein, human; D051844:alpha-Synuclein; C097188:polyglutamine; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000626:Aminopeptidases; C025579:enkephalin degrading enzyme; C092341:ATXN3 protein, human; D000067699:Ataxin-3; D046988:Proteasome Endopeptidase Complex