Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
Division of Nephrology, China Medical University Hospital, Taichung, Taiwan.
J Cell Biochem. 2020 Nov;121(11):4522-4534. doi: 10.1002/jcb.29669. Epub 2020 Feb 7.
Autophagy, an important cellular homeostatic mechanism regulates cell survival under stress and protects against acute kidney injury. However, the role of long noncoding RNA (lncRNA) in autophagy regulation in renal tubular cells (HK-2) is unclear. The study was aimed to understand the importance of lncRNA in hypoxia-induced autophagy in HK-2 cells. LncRNA eosinophil granule ontogeny transcript (EGOT) was identified as autophagy-associated lncRNA under hypoxia. The lncRNA EGOT expression was significantly downregulated in renal tubular cells during hypoxia-induced autophagy. Gain- and loss-of-EGOT functional studies revealed that EGOT overexpression reduced autophagy by downregulation of ATG7, ATG16L1, LC3II expressions and LC 3 puncta while EGOT knockdown reversed the suppression of autophagy. Importantly, RNA-binding protein, (ELAVL1)/Hu antigen R (HuR) binds and stabilizes the EGOT expression under normoxia and ATG7/16L1 expressions under hypoxia. Furthermore, HuR mediated stabilization of ATG7/16L1 expressions under hypoxia causes a decline in EGOT levels and thereby promotes autophagy. Altogether, the study first reveals the functional interplay of lncRNA EGOT and HuR on the posttranscriptional regulation of the ATG7/16L1 expressions. Thus, the HuR/EGOT/ATG7/16L1 axis is crucial for hypoxia-induced autophagy in renal tubular cells.
自噬是一种重要的细胞内稳态机制，可调节应激下的细胞存活并防止急性肾损伤。然而，长链非编码 RNA（lncRNA）在肾小管细胞（HK-2）中的自噬调控中的作用尚不清楚。本研究旨在了解 lncRNA 在 HK-2 细胞缺氧诱导自噬中的重要性。lncRNA 嗜酸性粒细胞颗粒发生转录物（EGOT）被鉴定为缺氧下与自噬相关的 lncRNA。在肾小管细胞缺氧诱导自噬过程中，lncRNA EGOT 的表达显著下调。EGOT 的功能获得和缺失研究表明，EGOT 过表达通过下调 ATG7、ATG16L1 和 LC3II 的表达和 LC3 斑点来减少自噬，而 EGOT 敲低逆转了自噬的抑制。重要的是，RNA 结合蛋白（ELAVL1）/Hu 抗原 R（HuR）在常氧条件下结合并稳定 EGOT 的表达，在缺氧条件下稳定 ATG7/16L1 的表达。此外，HuR 介导的 ATG7/16L1 表达在缺氧条件下的稳定导致 EGOT 水平下降，从而促进自噬。总之，该研究首次揭示了 lncRNA EGOT 和 HuR 在 ATG7/16L1 表达的转录后调节中的功能相互作用。因此，HuR/EGOT/ATG7/16L1 轴对于肾小管细胞缺氧诱导的自噬至关重要。
