Novel peroxisomal protease Tysnd1 processes PTS1- and PTS2-containing enzymes involved in β-oxidation of fatty acids

Kurochkin, Igor V.; Mizuno, Yumi; Konagaya, Akihiko; Sakaki, Yoshiyuki; Schönbach, Christian; Okazaki, Yasushi

doi:10.1038/sj.emboj.7601525

Cited by 90 publications

(85 citation statements)

References 46 publications

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“…Mammalian PTS2 proteins are thiolase, phytanoyl-CoA hydroxylase (PhyH), and alkylglycerone phosphate synthase (AGPS). After import of these preproteins, a PTS1 matrix protease removes the N-terminal PTS2 sequence, generating a smaller, mature protein (15). The relative increase in this maturation step should reflect the recovery of both PTS1 and PTS2 import observed in the previous experiments.…”

Section: Resultsmentioning

confidence: 99%

Recovery of PEX1-Gly843Asp peroxisome dysfunction by small-molecule compounds

Zhang

Chen

Jiralerspong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Zellweger spectrum disorder (ZSD) is a heterogeneous group of diseases with high morbidity and mortality caused by failure to assemble normal peroxisomes. There is no therapy for ZSD, but management is supportive. Nevertheless, one-half of the patients have a phenotype milder than classic Zellweger syndrome and exhibit a progressive disease course. Thus, patients would benefit if therapies became available and were instituted early. Recent reports indicate several interventions that result in partial peroxisome recovery in ZSD fibroblasts. To identify drugs that recover peroxisome functions, we expressed a GFP-peroxisome targeting signal 1 reporter in fibroblasts containing the common disease allele, PEX1-p.Gly843Asp. The GFP reporter remained cytosolic at baseline, and improvement in peroxisome functions was detected by the redistribution of the GFP reporter from the cytosol to the peroxisome. We established a high-content screening assay based on this phenotype assay and evaluated 2,080 small molecules. The cells were cultured in chemical for 2 days and then, were fixed and imaged by epifluorescent microscopy on a high-content imaging platform. We identified four compounds that partially recover matrix protein import, and we confirmed three using independent assays. Our results suggest that PEX1-p.G843D is a misfolded protein amenable to chaperone therapy.Zellweger spectrum | AAA ATPase | misfolded protein | chemical screening | pharmacologic chaperone

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Section: Resultsmentioning

confidence: 99%

Recovery of PEX1-Gly843Asp peroxisome dysfunction by small-molecule compounds

Zhang

Chen

Jiralerspong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…The PTS2 sequence is usually cleaved from the cargo protein after import into the peroxisome, a process that is not observed for PTS1-containing proteins (Tanaka et al, 2008). The protease that performs this cleavage has been identified as DEG15 in plants (Helm et al, 2007) and tysnd1 in mammals (Kurochkin et al, 2007). deg15 mutants have very mild peroxisome deficiency defects, suggesting that processing is not required for import (Lingard and Bartel, 2009).…”

Section: Pts2 Pathwaymentioning

confidence: 99%

Getting a camel through the eye of a needle: the import of folded proteins by peroxisomes

Lanyon‐Hogg

Warriner

Baker

2010

Biology of the Cell

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Peroxisomes are a family of organelles which have many unusual features. They can arise de novo from the endoplasmic reticulum by a still poorly characterized process, yet possess a unique machinery for the import of their matrix proteins. As peroxisomes lack DNA, their function, which is highly variable and dependent on developmental and/or environmental conditions, is determined by the post-translational import of specific metabolic enzymes in folded or oligomeric states. The two classes of matrix targeting signals for peroxisomal proteins [PTS1 (peroxisomal targeting signal 1) and PTS2] are recognized by cytosolic receptors [PEX5 (peroxin 5) and PEX7 respectively] which escort their cargo proteins to, or possibly across, the peroxisome membrane. Although the membrane translocation mechanism remains unclear, it appears to be driven by thermodynamically favourable binding interactions. Recycling of the receptors from the peroxisome membrane requires ATP hydrolysis for two linked processes: ubiquitination of PEX5 (and the PEX7 co-receptors in yeast) and the function of two peroxisome-associated AAA (ATPase associated with various cellular activities) ATPases, which play a role in recycling or turnover of the ubiquitinated receptors. This review summarizes and integrates recent findings on peroxisome matrix protein import from yeast, plant and mammalian model systems, and discusses some of the gaps in our understanding of this remarkable protein transport system.

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“…In these cells, peroxisomes were fluorescently labeled with DsRed2-Peroxi (a fluorescent peroxisome marker protein possessing a PTS1 sequence at the C terminus) (30). Using DsRed2-PTS1 cells, we further established a Tet-on HEK293 cell line (FL-PLA/AT-3-Tet-on cells), which can express FL-PLA/AT-3 in a tetracycline-dependent manner (31).…”

Section: Expression Of Pla/at-3 Rapidly Causesmentioning

confidence: 99%