Peroxisome Biogenesis Disorders

Honsho, Masanori; Okumoto, Kanji; Tamura, Shigehiko; Fujiki, Yukio

doi:10.1007/978-3-030-60204-8_4

Cited by 21 publications

(10 citation statements)

References 71 publications

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“…Peroxisomes are universal eukaryotic organelles housing various metabolic pathways and are functionally connected with other organelles such as mitochondria, chloroplasts, lipid bodies, and the endoplasmic reticulum. Severe peroxisomal dysfunction can cause fatal human genetic disorders and plant embryonic lethality (Honsho et al., 2020; Hu et al., 2012). The proteome and metabolism of peroxisomes vary significantly among different organisms, tissue types, and developmental stages, as well as in response to various environmental conditions (Corpas, 2019; Gabaldón, 2010; Pan et al., 2020; Reumann & Bartel, 2016).…”

Section: Introductionmentioning

confidence: 99%

Defining upstream enhancing and inhibiting sequence patterns for plant peroxisome targeting signal type 1 using large‐scale in silico and in vivo analyses

Deng

Feng

et al. 2022

The Plant Journal

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SUMMARY Peroxisomes are universal eukaryotic organelles essential to plants and animals. Most peroxisomal matrix proteins carry peroxisome targeting signal type 1 (PTS1), a C‐terminal tripeptide. Studies from various kingdoms have revealed influences from sequence upstream of the tripeptide on peroxisome targeting, supporting the view that positive charges in the upstream region are the major enhancing elements. However, a systematic approach to better define the upstream elements influencing PTS1 targeting capability is needed. Here, we used protein sequences from 177 plant genomes to perform large‐scale and in‐depth analysis of the PTS1 domain, which includes the PTS1 tripeptide and upstream sequence elements. We identified and verified 12 low‐frequency PTS1 tripeptides and revealed upstream enhancing and inhibiting sequence patterns for peroxisome targeting, which were subsequently validated in vivo. Follow‐up analysis revealed that nonpolar and acidic residues have relatively strong enhancing and inhibiting effects, respectively, on peroxisome targeting. However, in contrast to the previous understanding, positive charges alone do not show the anticipated enhancing effect and that both the position and property of the residues within these patterns are important for peroxisome targeting. We further demonstrated that the three residues immediately upstream of the tripeptide are the core influencers, with a ‘basic‐nonpolar‐basic’ pattern serving as a strong and universal enhancing pattern for peroxisome targeting. These findings have significantly advanced our knowledge of the PTS1 domain in plants and likely other eukaryotic species as well. The principles and strategies employed in the present study may also be applied to deciphering auxiliary targeting signals for other organelles.

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Section: Introductionmentioning

confidence: 99%

Defining upstream enhancing and inhibiting sequence patterns for plant peroxisome targeting signal type 1 using large‐scale in silico and in vivo analyses

Deng

Feng

et al. 2022

The Plant Journal

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“…Mitochondrial pathway disruption has been linked to a spectrum of pathophysiological conditions, from neurodegeneration and acute, chronic kidney and cardiovascular diseases, through to hepatocellular carcinoma and peroxisome biogenesis disorders. 6,[34][35][36] USP30 represents an actionable drug target of these conditions through its participation in PINK1/Parkin-mediated mitophagy, BAX/BAK-dependent apoptosis, oncogenesis, and pexophagy. 18,[37][38][39] USP30 regulates mitophagy by antagonizing Parkin-mediated ubiquitination and its inhibition has been shown to have significant therapeutic potential against PD and similar neurodegenerative disorders.…”

Section: Discussionmentioning

confidence: 99%

Structural Premise of Selective Deubiquitinase USP30 Inhibition by Small-Molecule Benzosulfonamides

O’Brien¹,

Jones²,

Guenther

et al. 2022

Preprint

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Dampening functional levels of the mitochondrial deubiquitylating enzyme USP30 has been suggested as an effective therapeutic strategy against neurodegenerative disorders such as Parkinson's Disease. USP30 inhibition may counteract the deleterious effects of impaired turnover of damaged mitochondria which is inherent to both familial and sporadic forms of the disease. Small-molecule inhibitors targeting USP30 are currently in development, but little is known about their precise nature of binding to the protein. We have integrated biochemical and structural approaches to gain novel mechanistic insights into USP30 inhibition by a small-molecule benzosulfonamide containing compound, 39. Activity-based protein profiling (ABPP) mass spectrometry confirmed target engagement, the high selectivity, and potency of 39 for USP30 against 49 other deubiquitylating enzymes in a neuroblastoma cell line. In vitro characterization of 39 enzyme kinetics infers slow and tight binding behavior, which is comparable with features of covalent modification of USP30. Finally, we blended hydrogen-deuterium exchange mass spectrometry and computational docking to elucidate the molecular architecture and geometry of USP30 complex formation with 39, identifying structural rearrangements at the cleft of the USP30 thumb and palm subdomains. These studies suggest that 39 binds to the thumb-palm cleft that guides the ubiquitin C-terminus into the active site, thereby preventing ubiquitin binding and isopeptide bond cleavage, and confirming its importance in the inhibitory process. Our data will pave the way for the design and development of next-generation inhibitors targeting USP30 and associated deubiquitinylases.

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“…Moreover, peroxisomes have been linked to cancer via their roles in aberrant metabolism and crosstalk with mitochondria (and associated mitochondrial dysfunction) in cancer [ 12 ]. In lung cancer aberrant metabolism is well documented [ 13 , 14 ], as is mitochondrial dysfunction [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Altered expression of ACOX2 in non-small cell lung cancer

et al. 2022

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Peroxisomes are organelles that play essential roles in many metabolic processes, but also play roles in innate immunity, signal transduction, aging and cancer. One of the main functions of peroxisomes is the processing of very-long chain fatty acids into metabolites that can be directed to the mitochondria. One key family of enzymes in this process are the peroxisomal acyl-CoA oxidases (ACOX1, ACOX2 and ACOX3), the expression of which has been shown to be dysregulated in some cancers. Very little is however known about the expression of this family of oxidases in non-small cell lung cancer (NSCLC). ACOX2 has however been suggested to be elevated at the mRNA level in over 10% of NSCLC, and in the present study using both standard and bioinformatics approaches we show that expression of ACOX2 is significantly altered in NSCLC. ACOX2 mRNA expression is linked to a number of mutated genes, and associations between ACOX2 expression and tumour mutational burden and immune cell infiltration were explored. Links between ACOX2 expression and candidate therapies for oncogenic driver mutations such as KRAS were also identified. Furthermore, levels of acyl-CoA oxidases and other associated peroxisomal genes were explored to identify further links between the peroxisomal pathway and NSCLC. The results of this biomarker driven study suggest that ACOX2 may have potential clinical utility in the diagnosis, prognosis and stratification of patients into various therapeutically targetable options.

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Peroxisome Biogenesis Disorders

Cited by 21 publications

References 71 publications

Defining upstream enhancing and inhibiting sequence patterns for plant peroxisome targeting signal type 1 using large‐scale in silico and in vivo analyses

Defining upstream enhancing and inhibiting sequence patterns for plant peroxisome targeting signal type 1 using large‐scale in silico and in vivo analyses

Structural Premise of Selective Deubiquitinase USP30 Inhibition by Small-Molecule Benzosulfonamides

Altered expression of ACOX2 in non-small cell lung cancer

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