期刊
EMBO MOLECULAR MEDICINE
卷 6, 期 8, 页码 1028-1042出版社
WILEY
DOI: 10.15252/emmm.201303809
关键词
Proteasome; SCD-EDS; VCP; zinc transporter; ZIP13
资金
- KAKENHI Grant of Japan Society for the Promotion of Science (JSPS)
- Life Science Foundation of Japan
- Japan Osteoporosis Foundation
- Targeted Proteins Research Program
- RIKEN Junior Research Associate Program
- Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT)
- Grants-in-Aid for Scientific Research [26660086, 26462324, 25462874] Funding Source: KAKEN
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(FLA), which contains a deletion of Phe-Leu-Ala. We demonstrated that both the ZIP13(G64D) and ZIP13(FLA) 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.
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