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Citation
Menzies, F.M., Hourez, R., Imarisio, S., Raspe, M., Sadiq, O., Chandraratna, D., O'Kane, C., Rock, K.L., Reits, E., Goldberg, A.L., Rubinsztein, D.C. (2010). Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy.  Hum. Mol. Genet. 19(23): 4573--4586.
FlyBase ID
FBrf0212250
Publication Type
Research paper
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.

PubMed ID
PubMed Central ID
PMC2972693 (PMC) (EuropePMC)
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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Hum. Mol. Genet.
    Title
    Human Molecular Genetics
    Publication Year
    1992-
    ISBN/ISSN
    0964-6906
    Data From Reference
    Alleles (8)
    Genes (3)
    Human Disease Models (1)
    Insertions (1)
    Transgenic Constructs (7)