RNA‐binding protein, human antigen R regulates hypoxia‐induced autophagy by targeting ATG7/ATG16L1 expressions and autophagosome formation

• Published in: Journal of cellular physiology Vol. 234; no. 5; pp. 7448 - 7458
• Main Authors: Palanisamy, Kalaiselvi, Tsai, Tsung‐Hsun, Yu, Tung‐Min, Sun, Kuo‐Ting, Yu, Shao‐Hua, Lin, Feng‐Yen, Wang, I‐Kuan, Li, Chi‐Yuan
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.05.2019
• Subjects: 3' Untranslated regions; 3' Untranslated Regions - physiology; acute kidney injury (AKI); Acute Kidney Injury - metabolism; Apoptosis; Apoptosis - physiology; ATG (autophagy‐related) proteins; autophagosome; Autophagosomes - metabolism; Autophagy; Autophagy - physiology; Autophagy-Related Protein 7 - metabolism; Autophagy-Related Proteins - metabolism; Bioinformatics; Cell Line; DNA nucleotidylexotransferase; HEK293 Cells; Humans; HuR; HuR protein; Hypoxia; Hypoxia - metabolism; Immunoprecipitation; Kidney - metabolism; Kidney Tubules, Proximal - metabolism; Microtubule-Associated Proteins - metabolism; mRNA; Phagocytosis; Proteins; Ribonucleic acid; RNA; RNA binding protein (RBP); RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; RNA-binding protein; RNA-Binding Proteins - metabolism; acute kidney injury (AKI); autophagy; HuR; ATG (autophagy-related) proteins; autophagosome; RNA binding protein (RBP)
• ISSN: 0021-9541; 1097-4652; 1097-4652
• DOI: 10.1002/jcp.27502

Autophagy, a prosurvival mechanism offers a protective role during acute kidney injury. We show novel findings on the functional role of RNA binding protein, HuR during hypoxia‐induced autophagy in renal proximal tubular cells‐2 (HK‐2). HK‐2 cells showed upregulated expressions of HuR and autophagy‐related proteins such as autophagy related 7 (ATG7), autophagy related 16 like 1 (ATG16L1), and LC3II under hypoxia. Increased autophagosome formation was visualized as LC3 puncta in hypoxic cells. Further, short hairpin‐RNA‐mediated loss of HuR function in HK‐2 cells significantly decreased ATG7 and ATG16L1 protein expressions. Bioinformatics prediction revealed HuR motif binding on the coding region of ATG7 and AU‐rich element at 3′UTR ATG16L1 messnger RNA (mRNA). The RNA immunoprecipitation study showed that HuR was predominantly associated with ATG7 and ATG16L1 mRNAs under hypoxia. In addition, HuR enhanced autophagosome formation by regulating LC3II expressions. These results show that HuR regulates ATG7 and ATG16L1 expressions and thereby mediate autophagy in HK‐2 cells. Importantly, HuR knockdown cells underwent apoptosis during hypoxia as observed through the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Collectively, these findings show the crucial role of HuR under hypoxia by regulating autophagy and suppressing apoptosis in renal tubular cells. Under hypoxic stress in renal tubular cells, HuR translocate into the cytosol and regulates autophagy related 7/autophagy related 16 like 1 expressions and autophagosome formation. HuR promotes autophagy and suppresses apoptosis during cellular adaption to hypoxic stress.