ZDHHC9-Mediated PKG1 Affects Osteogenesis by Regulating MAMs in T2DM.

B Y Li, G Q Ma, H D Gui, S J Zhou, Y X Liu, A L Wu, Q X He, J Y Chen, J Y Diao, D N Wu, X Xu, D J Zhang
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Abstract

Palmitoylation is recognized as a prevalent posttranslational modification of proteins, which is highlighted in recent studies as a key player in regulating protein stability, subcellular localization, membrane transport, and other cellular biological processes. However, its role in peri-implant osteogenesis under type 2 diabetes mellitus (T2DM) remains unclear. During this study, the in vitro high-glucose model based on MC3T3-E1 cells demonstrated that a high-glucose environment in vitro markedly inhibited osteoblasts proliferation and osteogenesis; meanwhile, ZDHHC9 emerged as a significantly upregulated protein. Then, Zdhhc9 knockdown improved the dysfunction of osteoblasts and peri-implant osteogenesis of T2DM mice. In addition, co-immunoprecipitation and fluorescence co-localization analysis revealed an interaction between ZDHHC9 and cyclic guanosine monophosphate (GMP)-dependent protein kinase G 1 (PKG1), and silencing of Prkg1 prevented the improvement in osteoblasts with Zdhhc9 knockdown. Furthermore, we verified that Zdhhc9 knockdown and Prkg1 silencing altered the distance between the endoplasmic reticulum and mitochondria and the expression of mitochondria-associated endoplasmic reticulum membranes (MAMs)-related proteins in osteoblasts. Collectively, our data show that ZDHHC9 could regulate MAMs through palmitoylation of PKG1 to induce osteoblast dysfunction in T2DM. ZDHHC9 might become a novel therapeutic target for peri-implant osteogenesis in diabetes patients.

zdhhc9介导的PKG1通过调节T2DM的MAMs影响成骨。
棕榈酰化被认为是一种普遍的蛋白质翻译后修饰,在最近的研究中被强调为调节蛋白质稳定性,亚细胞定位,膜运输和其他细胞生物学过程的关键角色。然而,其在2型糖尿病(T2DM)患者种植体周围成骨中的作用尚不清楚。在本研究中,基于MC3T3-E1细胞的体外高糖模型表明,体外高糖环境明显抑制成骨细胞的增殖和成骨;同时,ZDHHC9作为一个显著上调的蛋白出现。然后,敲低Zdhhc9可改善T2DM小鼠成骨细胞功能障碍和种植体周围成骨功能障碍。此外,共免疫沉淀和荧光共定位分析显示ZDHHC9与环鸟苷单磷酸(GMP)依赖性蛋白激酶g1 (PKG1)之间存在相互作用,Prkg1的沉默阻止了ZDHHC9敲除对成骨细胞的改善。此外,我们证实了Zdhhc9敲低和Prkg1沉默改变了成骨细胞内质网和线粒体之间的距离以及线粒体相关内质网膜(MAMs)相关蛋白的表达。综上所述,我们的数据表明ZDHHC9可以通过PKG1的棕榈酰化来调节MAMs,从而诱导T2DM的成骨细胞功能障碍。ZDHHC9可能成为糖尿病患者种植体周围成骨的新靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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