Molecular pathogenesis of spondylocheirodysplastic Ehlers-Danlos syndrome caused by mutant ZIP13 proteins.
Molecular pathogenesis of spondylocheirodysplastic Ehlers-Danlos syndrome caused by mutant ZIP13 proteins.
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DOI：
10.15252/emmm.201303809
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发表时间：
2014-08
影响因子：
11.1
通讯作者：
Fukada T
中科院分区：
文献类型：
--
作者：
Bin BH;Hojyo S;Hosaka T;Bhin J;Kano H;Miyai T;Ikeda M;Kimura-Someya T;Shirouzu M;Cho EG;Fukue K;Kambe T;Ohashi W;Kim KH;Seo J;Choi DH;Nam YJ;Hwang D;Fukunaka A;Fujitani Y;Yokoyama S;Superti-Furga A;Ikegawa S;Lee TR;Fukada T
锌转运蛋白ZIP 13在骨、牙齿和结缔组织发育中起关键作用，其功能障碍是导致Ehlers-Danlos综合征的脊椎手发育不良形式的原因（SCD-EDS，OMIM 612350）。在这里，我们报告了在人类患者中发现的两种不同突变ZIP 13蛋白引起的SCD-EDS的分子致病机制：ZIP 13 G64 D，其中氨基酸位置64处的Gly被Asp取代，以及ZIP 13 Δ弗拉，其中包含Phe-Leu-Ala的缺失。我们证明了ZIP 13 G64 D和ZIP 13 Δ弗拉蛋白水平均通过含缬氨素蛋白（VCP）连接的泛素蛋白酶体途径降解而降低。降解途径的抑制挽救了蛋白质表达水平，从而改善了细胞内锌稳态。我们的研究结果揭示了突变ZIP 13蛋白引起的致病机制。进一步阐明这些降解过程可能会导致新的治疗SCD-EDS的目标。
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: ZIP13G64D, in which Gly at amino acid position 64 is replaced by Asp, and ZIP13ΔFLA, which contains a deletion of Phe-Leu-Ala. We demonstrated that both the ZIP13G64D and ZIP13ΔFLA 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.