The zinc transporter protein ZIP13 plays critical roles in bone, tooth, and connective tissue development, and its dysfunction is responsible for the spondylocheirodysplastic form of Ehlers-Danlos syndrome (SCD-EDS, OMIM 612350). Here, we report the molecular pathogenic mechanism of SCD-EDS caused by two different mutant ZIP13 proteins found in human patients: ZIP13(G64D), in which Gly at amino acid position 64 is replaced by Asp, and ZIP13(ΔFLA), which contains a deletion of Phe-Leu-Ala. We demonstrated that both the ZIP13(G64D) and ZIP13(ΔFLA) protein levels are decreased by degradation via the valosin-containing protein (VCP)-linked ubiquitin proteasome pathway. The inhibition of degradation pathways rescued the protein expression levels, resulting in improved intracellular Zn homeostasis. Our findings uncover the pathogenic mechanisms elicited by mutant ZIP13 proteins. Further elucidation of these degradation processes may lead to novel therapeutic targets for SCD-EDS.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154131 | PMC |
| http://dx.doi.org/10.15252/emmm.201303809 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Drosophila ZIP13 over-expression or transferrin1 RNAi influences the muscle degeneration of Pink1 RNAi by elevating iron levels in mitochondria.
J Neurochem
March 2022
Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China.
Disruption of iron homeostasis in the brain of Parkinson's disease (PD) patients has been reported for many years, but the underlying mechanisms remain unclear. To investigate iron metabolism genes related to PTEN-induced kinase 1 (Pink1) and parkin (E3 ubiquitin ligase), two PD-associated proteins that function to coordinate mitochondrial turnover via induction of selective mitophagy, we conducted a genetic screen in Drosophila and found that altered expression of genes involved in iron metabolism, such as Drosophila ZIP13 (dZIP13) or transferrin1 (Tsf1), significantly influences the disease progression related to Pink1 but not parkin. Several phenotypes of Pink1 mutant and Pink1 RNAi but not parkin mutant were significantly rescued by over-expression (OE) of dZIP13 (dZIP13 OE) or silencing of Tsf1 (Tsf1 RNAi) in the flight muscles.
View Article and Find Full Text PDFDetailed analyses of the crucial functions of Zn transporter proteins in alkaline phosphatase activation.
J Biol Chem
April 2020
Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan. Electronic address:
Numerous zinc ectoenzymes are metalated by zinc and activated in the compartments of the early secretory pathway before reaching their destination. Zn transporter (ZNT) proteins located in these compartments are essential for ectoenzyme activation. We have previously reported that ZNT proteins, specifically ZNT5-ZNT6 heterodimers and ZNT7 homodimers, play critical roles in the activation of zinc ectoenzymes, such as alkaline phosphatases (ALPs), by mobilizing cytosolic zinc into these compartments.
View Article and Find Full Text PDFA distinctive sequence motif in the fourth transmembrane domain confers ZIP13 iron function in Drosophila melanogaster.
Biochim Biophys Acta Mol Cell Res
February 2020
State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing, China. Electronic address:
The zinc/iron permease (ZIP/SLC39A) family plays an important role in metal ion transport and is essential for diverse physiological processes. Members of the ZIP family function primarily in the influx of transition metal ions zinc and iron, into cytoplasm from extracellular space or intracellular organelles. The molecular determinants defining metal ion selectivity among ZIP family members remain unclear.
View Article and Find Full Text PDFDrosophila multicopper oxidase 3 is a potential ferroxidase involved in iron homeostasis.
Biochim Biophys Acta Gen Subj
August 2018
State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China; Beijing Institute for Brain Disorders, Beijing, China. Electronic address:
Multicopper oxidases (MCOs) are a specific group of enzymes that contain multiple copper centers through which different substrates are oxidized. Main members of MCO family include ferroxidases, ascorbate oxidases, and laccases. MCO type of ferroxidases is key to iron transport across the plasma membrane.
View Article and Find Full Text PDFMolecular pathogenesis of spondylocheirodysplastic Ehlers-Danlos syndrome caused by mutant ZIP13 proteins.
EMBO Mol Med
August 2014
Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry Showa University, Shinagawa, Japan Laboratory for Homeostatic Network, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
The zinc transporter protein ZIP13 plays critical roles in bone, tooth, and connective tissue development, and its dysfunction is responsible for the spondylocheirodysplastic form of Ehlers-Danlos syndrome (SCD-EDS, OMIM 612350). Here, we report the molecular pathogenic mechanism of SCD-EDS caused by two different mutant ZIP13 proteins found in human patients: ZIP13(G64D), in which Gly at amino acid position 64 is replaced by Asp, and ZIP13(ΔFLA), which contains a deletion of Phe-Leu-Ala. We demonstrated that both the ZIP13(G64D) and ZIP13(ΔFLA) protein levels are decreased by degradation via the valosin-containing protein (VCP)-linked ubiquitin proteasome pathway.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!