HRD1 prevents apoptosis in renal tubular epithelial cells by mediating eIF2α ubiquitylation and degradation
| Autor: | Dongming Su, Yifei Sun, Yujie Huang, Xiubin Liang, Min Li, Hui You, Yizhi Cao, Yanjiao Li, Hui Sun |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Proteasome Endopeptidase Complex Ubiquitin-Protein Ligases Immunology Eukaryotic Initiation Factor-2 Palmitic Acid Apoptosis Article Cell Line 03 medical and health sciences Cellular and Molecular Neuroscience Mice 0302 clinical medicine medicine Animals Humans Diabetic Nephropathies lcsh:QH573-671 bcl-2-Associated X Protein Kidney biology Chemistry Caspase 3 lcsh:Cytology Endoplasmic reticulum Ubiquitination Epithelial Cells Cell Biology Transfection Endoplasmic Reticulum Stress Ubiquitin ligase Cell biology Disease Models Animal 030104 developmental biology medicine.anatomical_structure Glucose Kidney Tubules Proteasome Gene Expression Regulation Proto-Oncogene Proteins c-bcl-2 Cell culture 030220 oncology & carcinogenesis Proteolysis biology.protein Signal transduction Signal Transduction |
| Zdroj: | Cell Death and Disease, Vol 8, Iss 12, Pp 1-11 (2017) Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|