Current advances in the function and biogenesis of peroxisomes and their roles in health and disease

Dahan, Noa; Francisco, Tânia; Falter, Christian; Rodrigues, Tony A.; Kalel, Vishal C.; Kunze, Markus; Hansen, Tobias; Schliebs, Wolfgang; Erdmann, Ralf

doi:10.1007/s00418-021-01982-1

Cited by 4 publications

(6 citation statements)

References 53 publications

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“…The proteins with a TMH are the endo- and lysosomal membrane protein TMEM192 with four transmembrane domains, and the single-spanning type II plasma membrane protein SGCD. There was no peroxisomal protein negatively affected by PEX3 depletion, which has to be interpreted in light of the facts that PEX19 and PEX3 are essential for peroxisome formation [ 37 , 38 ], and that PEX3 deficiency causes the complete absence of peroxisomes [ 42 , 43 , 44 ]. Together, these results raise the question of why PEX3 depletion from HeLa cells had hardly any effect on the cellular proteome.…”

Section: Discussionmentioning

confidence: 99%

“…Recent work identified the PEX19/PEX3-dependent pathway as a fourth pathway for the ER targeting of precursor polypeptides [ 35 , 36 ]. PEX3 (also termed peroxisomal biogenesis factor 3 or Peroxin-3) was first identified in yeast, and is a membrane protein with an N-terminal transmembrane domain and a large C-terminal domain, which faces the cytosol both in yeast and in humans [ 37 , 38 , 39 , 40 , 41 ]. Originally, it was characterized as a peroxisomal membrane protein, which cooperates with the cytosolic protein PEX19 in the targeting of peroxisomal membrane proteins to pre-existent peroxisomes and in the facilitation of their membrane insertion [ 38 , 40 ].…”

Section: Introductionmentioning

confidence: 99%

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Quantitative Proteomics and Differential Protein Abundance Analysis after the Depletion of PEX3 from Human Cells Identifies Additional Aspects of Protein Targeting to the ER

Zimmermann

Lang

Lerner

et al. 2021

IJMS

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Protein import into the endoplasmic reticulum (ER) is the first step in the biogenesis of around 10,000 different soluble and membrane proteins in humans. It involves the co- or post-translational targeting of precursor polypeptides to the ER, and their subsequent membrane insertion or translocation. So far, three pathways for the ER targeting of precursor polypeptides and four pathways for the ER targeting of mRNAs have been described. Typically, these pathways deliver their substrates to the Sec61 polypeptide-conducting channel in the ER membrane. Next, the precursor polypeptides are inserted into the ER membrane or translocated into the ER lumen, which may involve auxiliary translocation components, such as the TRAP and Sec62/Sec63 complexes, or auxiliary membrane protein insertases, such as EMC and the TMCO1 complex. Recently, the PEX19/PEX3-dependent pathway, which has a well-known function in targeting and inserting various peroxisomal membrane proteins into pre-existent peroxisomal membranes, was also found to act in the targeting and, putatively, insertion of monotopic hairpin proteins into the ER. These either remain in the ER as resident ER membrane proteins, or are pinched off from the ER as components of new lipid droplets. Therefore, the question arose as to whether this pathway may play a more general role in ER protein targeting, i.e., whether it represents a fourth pathway for the ER targeting of precursor polypeptides. Thus, we addressed the client spectrum of the PEX19/PEX3-dependent pathway in both PEX3-depleted HeLa cells and PEX3-deficient Zellweger patient fibroblasts by an established approach which involved the label-free quantitative mass spectrometry of the total proteome of depleted or deficient cells, as well as differential protein abundance analysis. The negatively affected proteins included twelve peroxisomal proteins and two hairpin proteins of the ER, thus confirming two previously identified classes of putative PEX19/PEX3 clients in human cells. Interestingly, fourteen collagen-related proteins with signal peptides or N-terminal transmembrane helices belonging to the secretory pathway were also negatively affected by PEX3 deficiency, which may suggest compromised collagen biogenesis as a hitherto-unknown contributor to organ failures in the respective Zellweger patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantitative Proteomics and Differential Protein Abundance Analysis after the Depletion of PEX3 from Human Cells Identifies Additional Aspects of Protein Targeting to the ER

Zimmermann

Lang

Lerner

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…The proteins with a TMH are the endo-and lysosomal membrane protein TMEM192 with four transmembrane domains and the single-spanning type II plasma membrane protein SGCD. There was no peroxisomal protein negatively affected by PEX3 depletion, which has to be interpreted in light of the facts that PEX19 and PEX3 are essential for peroxisome formation [37,38] and that PEX3-deficiency causes the complete absence of peroxisomes [42][43][44]. Together, these results raise the question why PEX3 depletion from HeLa cells had hardly any effect on the cellular proteome.…”

Section: Discussionmentioning

confidence: 87%

“…Recent work identified the PEX19/PEX3-dependent pathway as a fourth pathway for ER targeting of precursor polypeptides [35,36]. PEX3 (also termed peroxisomal biogenesis factor 3 or Peroxin-3) was first identified in yeast and is a membrane protein with a N-terminal transmembrane domain plus a large C-terminal domain, which is facing the cytosol both in yeast and in humans [37][38][39][40][41]. Originally, it was characterized as peroxisomal membrane protein, which cooperates with the cytosolic protein PEX19 in targeting of peroxisomal membrane proteins to pre-existent peroxisomes and in facilitating their membrane insertion [38,40].…”

Section: Introductionmentioning

confidence: 99%

Quantitative Proteomics and Differential Protein Abundance Analysis after Depletion of PEX3 from Human Cells Identifies Additional Aspects of Protein Targeting to the ER

Zimmermann¹,

Lang²,

Lerner³

et al. 2021

Preprint

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Protein import into the endoplasmic reticulum (ER) is the first step in the biogenesis of about 10,000 different soluble and membrane proteins in humans. It involves co- or post-translational targeting of precursor polypeptides to the ER and their subsequent membrane insertion or translocation. So far, three pathways for ER targeting of precursor polypeptides plus four pathways for ER targeting of mRNAs were described. Typically, these pathways deliver their substrates to the Sec61 polypeptide-conducting channel in the ER membrane. Next, the precursor polypeptides are inserted into the ER membrane or translocated into the ER lumen, which may involve auxiliary translocation components, such as the TRAP and Sec62/Sec63 complexes, or auxiliary membrane protein insertases, such as EMC and the TMCO1 complex. Recently, the PEX19/PEX3-dependent pathway, which has a well-known function in targeting and inserting various peroxisomal membrane proteins into pre-existent peroxisomal membranes, was also found to act in targeting and, putatively, inserting monotopic hairpin proteins into the ER. These either remain in the ER as resident ER membrane proteins or are pinched off from the ER as components of new lipid droplets. Therefore, the question arose if this pathway may play a more general role in ER protein targeting, i.e. represents a fourth pathway for ER targeting of precursor polypeptides. Thus, we addressed the client spectrum of the PEX19/PEX3-dependent pathway in both PEX3-depleted HeLa cells and PEX3-deficient Zellweger patient fibroblasts by an established approach, which involves label-free quantitative mass spectrometry of the total proteome of depleted or deficient cells and differential protein abundance analysis. The negatively affected proteins included twelve peroxisomal proteins and two hairpin proteins of the ER, thus confirming two previously identified classes of putative PEX19/PEX3-clients in human cells. Interestingly, fourteen collagen-related proteins with signal peptides or N-terminal transmembrane helices and belonging to the secretory pathway were also negatively affected by PEX3-deficiency, which may suggest compromised collagen biogenesis as a hitherto unknown contributor to organ failures in the respective Zellweger patients.

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“…Despite the presence in the peroxisome of the full enzymatic machinery to β-oxidize FAs, such oxidation normally is incomplete, and the final products of the peroxisomal β-oxidation are shuttled to mitochondria for complete oxidation to CO 2 , H 2 O, and final energy output. Some products of peroxisomal β-oxidation also may be used in other metabolic pathways (for example, by participating in the biosynthesis of the taurine and glycine conjugates, with subsequent export into the biliary ducts) [181].…”

Section: Role Of the Liver Mitochondria In The Development Of Cvd-promoting Dyslipidemiamentioning

confidence: 99%

Mitochondrial Lipid Homeostasis at the Crossroads of Liver and Heart Diseases

Dabravolski

Bezsonov

Baig

et al. 2021

IJMS

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The prevalence of NAFLD (non-alcoholic fatty liver disease) is a rapidly increasing problem, affecting a huge population around the globe. However, CVDs (cardiovascular diseases) are the most common cause of mortality in NAFLD patients. Atherogenic dyslipidemia, characterized by plasma hypertriglyceridemia, increased small dense LDL (low-density lipoprotein) particles, and decreased HDL-C (high-density lipoprotein cholesterol) levels, is often observed in NAFLD patients. In this review, we summarize recent genetic evidence, proving the diverse nature of metabolic pathways involved in NAFLD pathogenesis. Analysis of available genetic data suggests that the altered operation of fatty-acid β-oxidation in liver mitochondria is the key process, connecting NAFLD-mediated dyslipidemia and elevated CVD risk. In addition, we discuss several NAFLD-associated genes with documented anti-atherosclerotic or cardioprotective effects, and current pharmaceutical strategies focused on both NAFLD treatment and reduction of CVD risk.

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Current advances in the function and biogenesis of peroxisomes and their roles in health and disease

Cited by 4 publications

References 53 publications

Quantitative Proteomics and Differential Protein Abundance Analysis after the Depletion of PEX3 from Human Cells Identifies Additional Aspects of Protein Targeting to the ER

Quantitative Proteomics and Differential Protein Abundance Analysis after the Depletion of PEX3 from Human Cells Identifies Additional Aspects of Protein Targeting to the ER

Quantitative Proteomics and Differential Protein Abundance Analysis after Depletion of PEX3 from Human Cells Identifies Additional Aspects of Protein Targeting to the ER

Mitochondrial Lipid Homeostasis at the Crossroads of Liver and Heart Diseases

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