Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy

Fiona M. Menzies, Raphael Hourez, Sara Imarisio, Marcel Raspe, Oana Sadiq, Dhia Chandraratna, Cahir O'Kane, Kenneth L. Rock, Eric Reits, Alfred L. Goldberg, David C. Rubinsztein

Research output: Contribution to journalArticleAcademicpeer-review

60 Citations (Scopus)

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
Original languageEnglish
Pages (from-to)4573-4586
JournalHuman Molecular Genetics
Volume19
Issue number23
DOIs
Publication statusPublished - 2010

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