Molecular pathogenesis of Spondylocheirodysplastic Ehlers‐Danlos syndrome caused by mutant ZIP13 proteins

EMBO Molecular Medicine

Bum-Ho Bin⁷  Shintaro Hojyo⁸  Toshiaki Hosaka⁵  Jinhyuk Bhin²  Hiroki Kano¹⁰  Tomohiro Miyai⁹  Mariko Ikeda⁵  Tomomi Kimura-Someya⁵  Mikako Shirouzu⁵  Eun-Gyung Cho⁷  Kazuhisa Fukue⁴  Taiho Kambe⁴  Wakana Ohashi⁸  Kyu-Han Kim⁷  Juyeon Seo⁷  Dong-Hwa Choi³  Yeon-Ju Nam³  Daehee Hwang¹¹  Ayako Fukunaka^1,7  Yoshio Fujitani^1,7  Shigeyuki Yokoyama⁵  Andrea Superti-Furga^6,7  Shiro Ikegawa¹⁰  Tae Ryong Lee⁷ 

[1] Center for Beta-Cell Biology and Regeneration, Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan;Department of Chemical Engineering, POSTECH, Pohang, Republic of Korea;Gyeonggi Bio Center, Gyeonggi Institute of Science & Technology Promotion, Suwon, Republic of Korea;Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan;RIKEN Systems and Structural Biology Center, Yokohama, Japan;Department of Pediatrics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland;Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea;Laboratory for Homeostatic Network, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan;Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan;Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, Daegu, Republic of Korea

关键词: Proteasome;    SCD‐EDS;    VCP;    zinc transporter;    ZIP13;   

DOI  :  10.15252/emmm.201303809

来源: Wiley

【 摘 要 】

Abstract

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.

Synopsis

The Spondylocheirodysplastic Ehlers-Danlos syndrome pathogenic ZIP13 mutants are degraded by the ubiquitin-proteasome pathway. Inhibition of this pathway restores ZIP13 levels with consequent improvement of intracellular Zn homeostasis.

• The Spondylocheirodysplastic Ehlers-Danlos syndrome pathogenic ZIP13 mutant proteins: ZIP13G64D and ZIP13ΔFLA, are degraded by the ubiquitin-proteasome pathway.
• Valosin-containing protein (VCP) is involved in the degradation of the pathogenic mutant ZIP13 proteins.
• The reduced expression levels of the ZIP13 mutant proteins are rescued by inhibition of the degradation pathways, resulting in improved intracellular zinc homeostasis.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.