雌激素增加Setdb1细胞质定位以稳定Serpinh1并改善成骨细胞的蛋白稳态

IF 3.8 3区 医学 Q2 CELL BIOLOGY
Chunqing Han , Peiwen Wang , Junxing Ye , Ruijian Wang , Xian Shi , Guoqin Hu , Xiping Hu , Jin Shen , Mengqing Zhang , Xian Zhang , Yu Wu
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引用次数: 0

摘要

雌激素在表观遗传水平上调控成骨细胞的活性。Setdb1是一种表观遗传调节因子,在维持骨骼稳态中起作用。Setdb1显示细胞核和细胞质在细胞中的定位;然而,Setdb1的亚细胞分布和细胞质Setdb1在成骨细胞中的作用在很大程度上是未知的。这里,免疫荧光染色和免疫印迹分析显示,β-雌二醇处理增加了成骨细胞核Setdb1的稳定性,从而增加了Setdb1在细胞质中的分布。在β-雌二醇处理的MC3T3-E1细胞中,敲低Atf7ip表达增强了Setdb1的胞质定位,但Setdb1抑制剂(R,R)-59处理的细胞中Setdb1的胞质分布减少。此外,成熟成骨细胞中缺乏Atf7ip的卵巢切除(OVX)小鼠的骨微观结构优于OVX对照组。对Setdb1细胞质结合的蛋白质组学分析表明,Setdb1在成骨细胞细胞质中主要起调节蛋白稳态的作用。Setdb1与Serpinh1结合,Serpinh1是前胶原折叠和成熟的调节因子,并增强Serpinh1的稳定性。用Leptomycin B (LMB)或(R,R)-59处理细胞,阻断Setdb1细胞质定位,导致未折叠蛋白的积累和内质网(ER)应激的引发。这些发现揭示了细胞质Setdb1在调节β-雌二醇介导的成骨细胞稳态中的作用,这有助于进一步了解雌激素调节成骨细胞的作用机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Estrogen increases Setdb1 cytoplasmic localization to stabilize Serpinh1 and improve protein homeostasis in osteoblasts

Estrogen increases Setdb1 cytoplasmic localization to stabilize Serpinh1 and improve protein homeostasis in osteoblasts
Estrogen regulates osteoblast activity at the epigenetic level. Setdb1 is an epigenetic regulator that functions in skeleton homeostasis maintenance. Setdb1 shows nuclear and cytoplasm localization in cells; however, the subcellular distribution of Setdb1 and the role of cytoplasmic Setdb1 in osteoblasts are largely unknown. Here, immunofluorescence staining and immunoblotting analysis showed that the distribution of Setdb1 in the cytoplasm increased upon β-estradiol treatment by increasing nuclear Setdb1 stability in osteoblasts. In β-estradiol-treated MC3T3-E1 cells, knocking-down Atf7ip expression enhanced Setdb1 cytoplasmic localization, but the cytoplasmic distribution of Setdb1 decreased in cells treated with the Setdb1 inhibitor (R,R)-59. Moreover, ovariectomized (OVX) mice lacking Atf7ip in mature osteoblasts showed better bone microstructure than the OVX controls. The proteomic analysis of the cytoplasmic binding of Setdb1 showed that cytoplasmic Setdb1 in osteoblasts mainly functioned to regulate protein homeostasis. Setdb1 binds to Serpinh1, a regulator of pro-collagen folding and maturation, and enhances Serpinh1 stability. Interrupting Setdb1 cytoplasmic localization by treating the cells with Leptomycin B (LMB) or (R,R)-59 led to an accumulation of unfolded protein and the elicitation of endoplasmic reticulum (ER) stress. The findings revealed a previously unrecognized role of cytoplasmic Setdb1 in the regulation of β-estradiol-mediated osteoblast homeostasis, which could enhance the understanding of estrogen's mechanism of action in regulating osteoblasts.
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来源期刊
Molecular and Cellular Endocrinology
Molecular and Cellular Endocrinology 医学-内分泌学与代谢
CiteScore
9.00
自引率
2.40%
发文量
174
审稿时长
42 days
期刊介绍: Molecular and Cellular Endocrinology was established in 1974 to meet the demand for integrated publication on all aspects related to the genetic and biochemical effects, synthesis and secretions of extracellular signals (hormones, neurotransmitters, etc.) and to the understanding of cellular regulatory mechanisms involved in hormonal control.
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