HRD1 prevents apoptosis in renal tubular epithelial cells by mediating eIF2α ubiquitylation and degradation.
HRD1 prevents apoptosis in renal tubular epithelial cells by mediating eIF2α ubiquitylation and degradation.
复制标题
HRD1 通过介导 eIF2 α 泛素化和降解来防止肾小管上皮细胞凋亡
DOI：
10.1038/s41419-017-0002-y
复制
发表时间：
2017-12-11
影响因子：
9
通讯作者：
Liang X
中科院分区：
文献类型：
--
作者：
Huang Y;Sun Y;Cao Y;Sun H;Li M;You H;Su D;Li Y;Liang X
肾小管上皮细胞凋亡是与肾小管间质纤维化和其他肾脏疾病相关的致病性的一个关键特征。 HRD1 是调节细胞凋亡和细胞增殖等重要细胞过程的一个因子，它是一种 E3 泛素连接酶，通过促进其靶蛋白的泛素化和降解来发挥作用。然而，HRD1 作为肾小管上皮细胞凋亡调节因子的详细机制尚未确定。在我们之前的液相色谱-串联质谱 (LC-MS/MS) 研究 (Mol Endocrinol. 2016;30:600–613) 中，我们证明 HRD1 的一个底物是 eIF2α，它是内质网 (ER) 应激的 PERK-eIF2α-ATF4-CHOP 信号通路中的关键蛋白。在这里，我们发现，当棕榈酸（PA）或高葡萄糖（HG）诱导 HKC-8 细胞凋亡时，eIF2α 表达增加，HRD1 表达减少。糖尿病肾病 (DN) 小鼠肾组织中的 HRD1 表达也低于对照小鼠。 HRD1的强制表达也抑制了HKC-8细胞的凋亡，而HRD1的过表达则降低了磷酸化eIF2α和eIF2α的表达。进一步分析表明HRD1与eIF2α相互作用并促进其泛素化并被蛋白酶体降解。此外，经 PA 处理的 HKC-8 细胞的 HRD1 保护因 Myc-eIF2α 转染而减弱。因此，HRD1 泛素化 eIF2α 可保护肾小管上皮细胞免受 HG 和 PA 引起的凋亡，这表明了治疗预防肾小管间质损伤的新上游靶点。
Apoptosis of renal tubular epithelial cells is a key feature of the pathogenicity associated with tubulointerstitial fibrosis and other kidney diseases. One factor that regulates important cellular processes like apoptosis and cell proliferation is HRD1, an E3 ubiquitin ligase that acts by promoting ubiquitylation and degradation of its target protein. However, the detailed mechanisms by which HRD1 acts as a regulator of apoptosis in renal tubular epithelial cells have not been established. In our previous liquid chromatography-tandem mass spectrometry (LC-MS/MS) study (Mol Endocrinol. 2016;30:600–613), we demonstrated that one substrate of HRD1 was eIF2α, a critical protein in the PERK-eIF2α-ATF4-CHOP signaling pathway of endoplasmic reticulum (ER) stress. Here, we show that eIF2α expression was increased and HRD1 expression decreased when apoptosis was induced in HKC-8 cells by palmitic acid (PA) or high glucose (HG). HRD1 expression was also lower in kidney tissues from mice with diabetic nephropathy (DN) than in control mice. Forced expression of HRD1 also inhibited apoptosis in HKC-8 cells, while HRD1 overexpression decreased the expression of phosphorylated eIF2α and eIF2α. Further analysis indicated that HRD1 interacted with eIF2α and promoted its ubiquitylation and degradation by the proteasome. Moreover, the HRD1 protection of PA-treated HKC-8 cells was blunted by transfection with Myc-eIF2α. Thus, eIF2α ubiquitylation by HRD1 protects tubular epithelial cells from apoptosis caused by HG and PA, indicating a novel upstream target for therapeutic prevention of renal tubulointerstitial injury.
登录
查看更多内容
DOI：
10.1042/bcj20160582
发表时间：
2017-02-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Preston GM;Brodsky JL
通讯作者：
Brodsky JL
Hrd1参与肾纤维化中I型胶原合成的调节
影响因子：
4.3
作者：
Li, Lei;Shen, Yachen;Liang, Xiubin
通讯作者：
Liang, Xiubin
乙酰辅酶 A 羧化酶 2 抑制可通过自噬将人近端肾小管细胞从棕榈酸诱导的脂毒性中拯救出来。
DOI：
10.1016/j.bbrc.2015.05.070
发表时间：
2015-07-31
影响因子：
3.1
作者：
Xin, Wei;Zhao, Xu;Wan, Qiang
通讯作者：
Wan, Qiang
影响因子：
4.6
作者：
Jiang XS;Chen XM;Wan JM;Gui HB;Ruan XZ;Du XG
通讯作者：
Du XG
影响因子：
--
作者：
Liu SH;Wu CT;Huang KH;Wang CC;Guan SS;Chen LP;Chiang CK
通讯作者：
Chiang CK