Interaction between PSMD10 and GRP78 accelerates endoplasmic reticulum stress-mediated hepatic apoptosis induced by homocysteine.
Interaction between PSMD10 and GRP78 accelerates endoplasmic reticulum stress-mediated hepatic apoptosis induced by homocysteine.
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PSMD10 和 GRP78 之间的相互作用加速同型半胱氨酸诱导的内质网应激介导的肝细胞凋亡
DOI：
10.1186/s13099-021-00455-z
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发表时间：
2021-10-19
期刊：
影响因子：
4.2
通讯作者：
Jiang Y
中科院分区：
文献类型：
--
作者：
Xiao K;Ma S;Xu L;Ding N;Zhang H;Xie L;Xu L;Jiao Y;Zhang H;Jiang Y
肝脏在同型半胱氨酸（homocysteine，Hcy）的产生和代谢中起着重要作用，而Hcy与肝损伤有关。在我们以前的工作中，我们证实了同型半胱氨酸可以通过激活内质网（ER）应激引起肝损伤。然而，其潜在机制在很大程度上仍然未知。本研究通过高蛋氨酸饲料喂养cbs+/−小鼠，建立了Hcy诱导的肝损伤模型，发现cbs+/−小鼠肝脏中经常出现大量肝细胞排列紊乱和肝细胞间隙扩大，并伴有凋亡相关蛋白表达水平升高。此外，Hcy可激活cbs+/−小鼠和肝细胞中的ER应激。在机制上，Hcy促进肝细胞中蛋白酶体26 S亚基非ATP酶10（PSMD 10）的表达水平;并且当Hcy处理下肝细胞中PSMD 10沉默时，ER应激指标和凋亡相关蛋白的表达被显著抑制。生物信息学分析和荧光素酶报告基因分析表明，PSMD 10是miR-212- 5 p的靶基因。结论miR-212- 5 p过表达可抑制Hcy诱导的ER应激介导的肝细胞凋亡。通过免疫共沉淀实验，我们发现PSMD 10和GRP 78之间的相互作用促进了Hcy诱导的内质网应激介导的肝细胞凋亡。我们的研究结果表明，miR-212- 5 p直接靶向PSMD 10，随后激活ER应激，促进Hcy诱导的肝细胞凋亡。我们认为内源性PSMD 10与GRP 78相互作用调节内质网应激。本研究为同型半胱氨酸致肝损伤的治疗提供了新的靶点。在线版本包含补充材料，可通过10.1186/s13099-021-00455-z获得。
The liver plays an important role in production and metabolism of homocysteine (Hcy), which has been reported to be involved in liver injury. In our previous work, we confirm that Hcy can induce liver injury by activating endoplasmic reticulum (ER) stress. However, the underlying mechanisms remain largely unknown. In present study, we established the Hcy-induced liver injury model by feeding cbs+/− mice with high methionine diet, and found that a considerable mass of disordered arrangement of hepatocytes and enlarged space between hepatocytes were frequently occurred in the liver of cbs+/− mice, accompanied with elevated expression levels of apoptosis-related proteins. In addition, Hcy could activate ER stress both in cbs+/− mice and hepatocytes. Mechanistically, Hcy promoted the expression levels of proteasome 26S subunit non-ATPase 10 (PSMD10) in hepatocytes; and the expression of ER stress indicators and apoptosis-associated proteins were significantly suppressed when PSMD10 was silenced in hepatocytes under Hcy treatment. Moreover, bioinformatics analysis and luciferase reporter assay demonstrated that PSMD10 was a target gene of miR-212-5p. Consistently, miR-212-5p overexpression could inhibit ER stress-mediated apoptosis of hepatocytes under Hcy treatment. With the help of co-immunoprecipitation assay, we identified that the interaction between PSMD10 and GRP78 accelerated ER stress-mediated hepatic apoptosis induced by Hcy. Our findings indicate that miR-212-5p directly targets PSMD10 and subsequently activates ER stress to promote Hcy-induced apoptosis of hepatocytes. We propose that endogenous PSMD10 physically interacts with GRP78 to regulate ER stress. Our study may provide the therapeutic target for the liver injury induced by Hcy. The online version contains supplementary material available at 10.1186/s13099-021-00455-z.
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