Caspase-mediated processing of TRBP regulates apoptosis during viral infection

Nucleic Acids Res. 2024 May 22;52(9):5209-5225. doi: 10.1093/nar/gkae246.


RNA silencing is a post-transcriptional gene-silencing mechanism mediated by microRNAs (miRNAs). However, the regulatory mechanism of RNA silencing during viral infection is unclear. TAR RNA-binding protein (TRBP) is an enhancer of RNA silencing that induces miRNA maturation by interacting with the ribonuclease Dicer. TRBP interacts with a virus sensor protein, laboratory of genetics and physiology 2 (LGP2), in the early stage of viral infection of human cells. Next, it induces apoptosis by inhibiting the maturation of miRNAs, thereby upregulating the expression of apoptosis regulatory genes. In this study, we show that TRBP undergoes a functional conversion in the late stage of viral infection. Viral infection resulted in the activation of caspases that proteolytically processed TRBP into two fragments. The N-terminal fragment did not interact with Dicer but interacted with type I interferon (IFN) signaling modulators, such as protein kinase R (PKR) and LGP2, and induced ER stress. The end results were irreversible apoptosis and suppression of IFN signaling. Our results demonstrate that the processing of TRBP enhances apoptosis, reducing IFN signaling during viral infection.

MeSH terms

  • Apoptosis* / genetics
  • Caspases* / genetics
  • Caspases* / metabolism
  • Cell Line
  • Endoplasmic Reticulum Stress / genetics
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Interferon Type I / genetics
  • Interferon Type I / metabolism
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • RNA-Binding Proteins* / genetics
  • RNA-Binding Proteins* / metabolism
  • Ribonuclease III / genetics
  • Ribonuclease III / metabolism
  • Signal Transduction
  • Virus Diseases / genetics
  • Virus Diseases / metabolism
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism


  • trans-activation responsive RNA-binding protein
  • EIF2AK2 protein, human