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J Biol Chem. 2012 May 18;287(21):17471-82. doi: 10.1074/jbc.M112.352781. Epub 2012 Mar 27.

Cathepsins L and Z are critical in degrading polyglutamine-containing proteins within lysosomes.

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1
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.

Abstract

In neurodegenerative diseases caused by extended polyglutamine (polyQ) sequences in proteins, aggregation-prone polyQ proteins accumulate in intraneuronal inclusions. PolyQ proteins can be degraded by lysosomes or proteasomes. Proteasomes are unable to hydrolyze polyQ repeat sequences, and during breakdown of polyQ proteins, they release polyQ repeat fragments for degradation by other cellular enzymes. This study was undertaken to identify the responsible proteases. Lysosomal extracts (unlike cytosolic enzymes) were found to rapidly hydrolyze polyQ sequences in peptides, proteins, or insoluble aggregates. Using specific inhibitors against lysosomal proteases, enzyme-deficient extracts, and pure cathepsins, we identified cathepsins L and Z as the lysosomal cysteine proteases that digest polyQ proteins and peptides. RNAi for cathepsins L and Z in different cell lines and adult mouse muscles confirmed that they are critical in degrading polyQ proteins (expanded huntingtin exon 1) but not other types of aggregation-prone proteins (e.g. mutant SOD1). Therefore, the activities of these two lysosomal cysteine proteases are important in host defense against toxic accumulation of polyQ proteins.

PMID:
22451661
PMCID:
PMC3366842
DOI:
10.1074/jbc.M112.352781
[Indexed for MEDLINE]
Free PMC Article
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