Rotavirus-induced lncRNA SLC7A11-AS1 promotes ferroptosis by targeting cystine/glutamate antiporter xCT (SLC7A11) to facilitate virus infection

Virus Res. 2024 Jan 2:339:199261. doi: 10.1016/j.virusres.2023.199261. Epub 2023 Nov 14.

Abstract

Rotavirus (RV) is the primary etiological agent of virus-associated gastroenteritis in infants, causing 200,000 childhood death annually. Despite the availability of vaccines, rotaviral diarrhea continues to be a severe issue in underdeveloped nations in Asia and Africa. The situation demands continual studies on host-rotavirus interactions to understand disease pathogenesis and develop effective antiviral therapeutics. Long non-coding RNAs (lncRNAs), which are a subset of non-coding RNAs of more than 200 nucleotides in length, are reported to play a regulatory function in numerous viral infections. Virus infection often alters the host transcriptome including lncRNA that are differentially expressed either to play an antiviral role or to be advantageous towards virus propagation. In the current study, qPCR array-based expression profiling of host lncRNAs was performed in rotavirus-infected HT-29 cells that identified the lncRNA SLC7A11-AS1 to be upregulated during RV infection. Knockdown of SLC7A11-AS1 conspicuously reduced RV titers implying its pro-viral significance. RV-induced SLC7A11-AS1 downregulates the gene SLC7A11/xCT that encodes the light chain subunit of the system XC- cystine-glutamate exchange transporter, leading to decrease in intracellular glutathione level and increase in lipid peroxidation, which are signature features of ferroptotic pathway. Ectopic expression of xCT also abrogated RV infection by reversing the virus optimized levels of intracellular GSH and lipid ROS levels. Cumulatively, the study reveals that RV infection triggers ferroptotic cell death via SLC7A11-AS1/xCT axis to facilitate its own propagation.

Keywords: Glutathione; Lipid peroxidation; ROS; Rotavirus; SLC7A11-AS1; lncRNA; xCT.

MeSH terms

  • Amino Acid Transport System y+ / genetics
  • Amino Acid Transport System y+ / metabolism
  • Antiviral Agents
  • Cell Line, Tumor
  • Child
  • Cystine / metabolism
  • Ferroptosis* / genetics
  • Glutamic Acid / metabolism
  • Glutathione / metabolism
  • Humans
  • RNA, Long Noncoding* / genetics
  • Rotavirus Infections* / metabolism
  • Rotavirus Infections* / virology
  • Rotavirus* / genetics
  • Rotavirus* / metabolism

Substances

  • Amino Acid Transport System y+
  • Antiviral Agents
  • Cystine
  • Glutamic Acid
  • Glutathione
  • RNA, Long Noncoding
  • SLC7A11 protein, human