Stabilization of Cx43 mRNA via RNA-binding protein HuR regulated by polyamines enhances intestinal epithelial barrier function

Shelley R. Wang, Caroline G. Mallard, Cassandra A. Cairns, Hee Kyoung Chung, Dongyoon Yoo, Suraj K. Jaladanki, Lan Xiao, Jian Ying Wang

Research output: Contribution to journalArticlepeer-review

Abstract

Gut barrier dysfunction occurs commonly in patients with critical disorders, leading to the translocation of luminal toxic substances and bacteria to the bloodstream. Connexin 43 (Cx43) acts as a gap junction protein and is crucial for intercellular communication and the diffusion of nutrients. The levels of cellular Cx43 are tightly regulated by multiple factors, including polyamines, but the exact mechanism underlying the control of Cx43 expression remains largely unknown. The RNA-binding protein HuR regulates the stability and translation of target mRNAs and is involved in many aspects of intestinal epithelial pathobiology. Here we show that HuR directly bound to Cx43 mRNA via its 30-untranslated region in intestinal epithelial cells (IECs) and this interaction enhanced Cx43 expression by stabilizing Cx43 mRNA. Depletion of cellular polyamines inhibited the [HuR/Cx43 mRNA] complex and decreased the level of Cx43 protein by destabilizing its mRNA, but these changes were prevented by ectopic overexpression of HuR. Polyamine depletion caused intestinal epithelial barrier dysfunction, which was reversed by ectopic Cx43 overexpression. Moreover, overexpression of checkpoint kinase 2 in polyamine-deficient cells increased the [HuR/Cx43 mRNA] complex, elevated Cx43 levels, and promoted barrier function. These findings indicate that Cx43 mRNA is a novel target of HuR in IECs and that polyamines regulate Cx43 mRNA stability via HuR, thus playing a critical role in the maintenance of intestinal epithelial barrier function.

Original languageEnglish
Pages (from-to)G518-G527
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume325
Issue number6
DOIs
StatePublished - Dec 2023
Externally publishedYes

Keywords

  • RNA-binding proteins
  • gut barrier function
  • intestinal epithelial cells
  • mRNA stability
  • polyamines

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