RRC ID 22705
著者 Menzies FM, Hourez R, Imarisio S, Raspe M, Sadiq O, Chandraratna D, O'Kane C, Rock KL, Reits E, Goldberg AL, Rubinsztein DC.
タイトル Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy.
ジャーナル Hum Mol Genet
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.
巻・号 19(23)
ページ 4573-86
公開日 2010-12-1
DOI 10.1093/hmg/ddq385
PII ddq385
PMID 20829225
PMC PMC2972693
MeSH Aminopeptidases / genetics Aminopeptidases / metabolism* Animals Ataxin-3 Autophagy* Cell Line Drosophila Gene Knockdown Techniques Humans Huntingtin Protein Male Mice Microtubule-Associated Proteins / genetics Microtubule-Associated Proteins / metabolism Nerve Tissue Proteins / genetics Nerve Tissue Proteins / metabolism Nuclear Proteins / genetics Nuclear Proteins / metabolism Peptide Fragments / metabolism Peptides / metabolism* Proteasome Endopeptidase Complex / metabolism RNA Interference Repressor Proteins / genetics Repressor Proteins / metabolism Superoxide Dismutase / genetics Superoxide Dismutase / metabolism Superoxide Dismutase-1 alpha-Synuclein / genetics alpha-Synuclein / metabolism
IF 5.101
引用数 47
WOS 分野 GENETICS & HEREDITY BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
ショウジョウバエ 1009R-2 1009R-3