Interaction between HuR and circPABPN1 Modulates Autophagy in the Intestinal Epithelium by Altering ATG16L1 Translation

ABSTRACT

Intestinal epithelial autophagy is crucial for host defense against invasive pathogens, and defects in this process occur frequently in patients with inflammatory bowel disease (IBD) and other mucosal disorders, but the exact mechanism that activates autophagy is poorly defined. Here, we investigated the role of RNA-binding protein HuR (human antigen R) in the posttranscriptional control of autophagy-related genes (ATGs) in the intestinal epithelium. We found that targeted deletion of HuR in intestinal epithelial cells (IECs) specifically decreased the levels of ATG16L1 in the intestinal mucosa. Intestinal mucosa from patients with IBD exhibited reduced levels of both HuR and ATG16L1. HuR directly interacted with Atg16l1 mRNA via its 3′ untranslated region and enhanced ATG16L1 translation, without affecting Atg16l1 mRNA stability. Circular RNA circPABPN1 blocked HuR binding to Atg16l1 mRNA and lowered ATG16L1 production. HuR silencing in cultured IECs also prevented rapamycin-induced autophagy, which was abolished by overexpressing ATG16L1. These findings indicate that HuR regulates autophagy by modulating ATG16L1 translation via interaction with circPABPN1 in the intestinal epithelium.

KEYWORDS:

• IBD
• mucosal defense
• RNA-binding proteins
• circular RNAs
• epithelial homeostasis

SUPPLEMENTAL MATERIAL

Supplemental material is available online only.

ACKNOWLEDGMENTS

Xiao-Xue Li and Lan Xiao performed most experiments and summarized data. Hee Kyoung Chung, Xiang-Xue Ma, Xiangzheng Liu, Jia-Le Song, and Cindy Z. Jin participated in in vivo experiments and RNA-binding assays. Jaladanki N. Rao and Myriam Gorospe participated in experiments using human tissues and data analysis. Jian-Ying Wang designed experiments, analyzed data, prepared figures, and drafted the manuscript.

This work was supported by Merit Review Awards (to J.-Y.W. and J.N.R.) from the U.S. Department of Veterans Affairs, by grants from National Institutes of Health (NIH) (DK57819, DK61972, and DK68491 to J.-Y.W.), and by funding from the National Institute on Aging Intramural Research Program, NIH (to M.G.).

Jian-Ying Wang is a senior research career scientist at the Biomedical Laboratory Research and Development Service, U.S. Department of Veterans Affairs. The remaining authors disclose no conflicts.