The deubiquitination of the PTS1-import receptor Pex5p is required for peroxisomal matrix protein import

Magraoui, Fouzi El; Brinkmeier, Rebecca; Mastalski, Thomas; Hupperich, Alexander; Strehl, Christofer; Schwerter, Daniel; Girzalsky, Wolfgang; Meyer, Helmut E.; Warscheid, Bettina; Erdmann, Ralf; Platta, Harald W.

doi:10.1016/j.bbamcr.2018.11.002

Cited by 14 publications

(8 citation statements)

References 74 publications

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“…In contrast to the aforementioned TPR receptors of cellular membranes, the cytosolic TPR receptor Pex5 does not recognize negatively charged EEVD motifs of chaperones, but the peroxisomal targeting signal 1 (PTS1) which is defined by a C-terminal peptide with the consensus sequence Ser-Lys-Leu-COO − [ 86 , 87 , 88 ].…”

Section: Evolution Of Tom70mentioning

confidence: 99%

The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity

Kreimendahl

Rassow

2020

IJMS

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Tom70 is a versatile adaptor protein of 70 kDa anchored in the outer membrane of mitochondria in metazoa, fungi and amoeba. The tertiary structure was resolved for the Tom70 of yeast, showing 26 α-helices, most of them participating in the formation of 11 tetratricopeptide repeat (TPR) motifs. Tom70 serves as a docking site for cytosolic chaperone proteins and co-chaperones and is thereby involved in the uptake of newly synthesized chaperone-bound proteins in mitochondrial biogenesis. In yeast, Tom70 additionally mediates ER-mitochondria contacts via binding to sterol transporter Lam6/Ltc1. In mammalian cells, TOM70 promotes endoplasmic reticulum (ER) to mitochondria Ca2+ transfer by association with the inositol-1,4,5-triphosphate receptor type 3 (IP3R3). TOM70 is specifically targeted by the Bcl-2-related protein MCL-1 that acts as an anti-apoptotic protein in macrophages infected by intracellular pathogens, but also in many cancer cells. By participating in the recruitment of PINK1 and the E3 ubiquitin ligase Parkin, TOM70 can be implicated in the development of Parkinson’s disease. TOM70 acts as receptor of the mitochondrial antiviral-signaling protein (MAVS) and thereby participates in the corresponding system of innate immunity against viral infections. The protein encoded by Orf9b in the genome of SARS-CoV-2 binds to TOM70, probably compromising the synthesis of type I interferons.

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Section: Evolution Of Tom70mentioning

confidence: 99%

The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity

Kreimendahl

Rassow

2020

IJMS

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“…After cargo release, Pex5 proteins are recycled from the peroxisome to the cytosol. Recycling involves ubiquitination, unfolding, energy provided by the AAA-ATPases Pex1 and Pex6, and deubiquitination ( Miyata and Fujiki, 2005 ; Platta et al, 2005 ; Platta et al, 2007 ; Gardner et al, 2018 ; Pedrosa et al, 2018 ; El Magraoui et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Two Pex5 Proteins With Different Cargo Specificity Are Critical for Peroxisome Function in Ustilago maydis

Ast

Bäcker

Bittner

et al. 2022

Front. Cell Dev. Biol.

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Peroxisomes are dynamic multipurpose organelles with a major function in fatty acid oxidation and breakdown of hydrogen peroxide. Many proteins destined for the peroxisomal matrix contain a C-terminal peroxisomal targeting signal type 1 (PTS1), which is recognized by tetratricopeptide repeat (TPR) proteins of the Pex5 family. Various species express at least two different Pex5 proteins, but how this contributes to protein import and organelle function is not fully understood. Here, we analyzed truncated and chimeric variants of two Pex5 proteins, Pex5a and Pex5b, from the fungus Ustilago maydis. Both proteins are required for optimal growth on oleic acid-containing medium. The N-terminal domain (NTD) of Pex5b is critical for import of all investigated peroxisomal matrix proteins including PTS2 proteins and at least one protein without a canonical PTS. In contrast, the NTD of Pex5a is not sufficient for translocation of peroxisomal matrix proteins. In the presence of Pex5b, however, specific cargo can be imported via this domain of Pex5a. The TPR domains of Pex5a and Pex5b differ in their affinity to variations of the PTS1 motif and thus can mediate import of different subsets of matrix proteins. Together, our data reveal that U. maydis employs versatile targeting modules to control peroxisome function. These findings will promote our understanding of peroxisomal protein import also in other biological systems.

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“…Next, the functional activity of peroxisomes of the same strains was analyzed by monitoring cell growth in liquid oleate medium as relative growth efficiency compared to WT cells ( Figure 1F, upper diagram). This method is relatively sensitive and should be able to detect minor changes in growth dynamics [18]. However, the value for pex1∆ cells did not improve with the additional deletion of ATG36.…”

Section: Resultsmentioning

confidence: 99%

The Peroxisomal PTS1-Import Defect of PEX1- Deficient Cells Is Independent of Pexophagy in Saccharomyces cerevisiae

Mastalski

Brinkmeier

Platta

2020

IJMS

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The important physiologic role of peroxisomes is shown by the occurrence of peroxisomal biogenesis disorders (PBDs) in humans. This spectrum of autosomal recessive metabolic disorders is characterized by defective peroxisome assembly and impaired peroxisomal functions. PBDs are caused by mutations in the peroxisomal biogenesis factors, which are required for the correct compartmentalization of peroxisomal matrix enzymes. Recent work from patient cells that contain the Pex1(G843D) point mutant suggested that the inhibition of the lysosome, and therefore the block of pexophagy, was beneficial for peroxisomal function. The resulting working model proposed that Pex1 may not be essential for matrix protein import at all, but rather for the prevention of pexophagy. Thus, the observed matrix protein import defect would not be caused by a lack of Pex1 activity, but rather by enhanced removal of peroxisomal membranes via pexophagy. In the present study, we can show that the specific block of PEX1 deletion-induced pexophagy does not restore peroxisomal matrix protein import or the peroxisomal function in beta-oxidation in yeast. Therefore, we conclude that Pex1 is directly and essentially involved in peroxisomal matrix protein import, and that the PEX1 deletion-induced pexophagy is not responsible for the defect in peroxisomal function. In order to point out the conserved mechanism, we discuss our findings in the context of the working models of peroxisomal biogenesis and pexophagy in yeasts and mammals.

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The deubiquitination of the PTS1-import receptor Pex5p is required for peroxisomal matrix protein import

Cited by 14 publications

References 74 publications

The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity

The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity

Two Pex5 Proteins With Different Cargo Specificity Are Critical for Peroxisome Function in Ustilago maydis

The Peroxisomal PTS1-Import Defect of PEX1- Deficient Cells Is Independent of Pexophagy in Saccharomyces cerevisiae

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