RNase L Induces Expression of A Novel Serine/Threonine Protein Kinase, DRAK1, to Promote Apoptosis

Int J Mol Sci. 2019 Jul 19;20(14):3535. doi: 10.3390/ijms20143535.


Apoptosis of virus-infected cells is an effective antiviral mechanism in addition to interferon induction to establish antiviral state to restrict virus spread. The interferon-inducible 2'-5' oligoadenylate synthetase/RNase L pathway results in activation of RNase L in response to double stranded RNA and cleaves diverse RNA substrates to amplify interferon induction and promote apoptosis. Here we show that RNase L induces expression of Death-associated protein kinase-Related Apoptosis-inducing protein Kinase 1 (DRAK1), a member of the death-associated protein kinase family and interferon-signaling pathway is required for induction. Overexpression of DRAK1 triggers apoptosis in the absence of RNase L activation by activating c-Jun N-terminal kinase (JNK), translocation of BCL2 Associated X (Bax) to the mitochondria accompanied by cytochrome C release and loss of mitochondrial membrane potential promoting cleavage of caspase 3 and Poly(ADP-Ribose) Polymerase 1 (PARP). Inhibitors of JNK and caspase 3 promote survival of DRAK1 overexpressing cells demonstrating an important role of JNK signaling pathway in DRAK1-mediated apoptosis. DRAK1 mutant proteins that lack kinase activity or nuclear localization fail to induce apoptosis highlighting the importance of cellular localization and kinase function in promoting cell death. Our studies identify DRAK1 as a mediator of RNase L-induced apoptosis.

Keywords: DRAK1; JNK; RNase L; apoptosis; interferon signaling.

MeSH terms

  • Apoptosis / genetics*
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / metabolism
  • Caspase 3 / metabolism
  • Cell Nucleus / metabolism
  • Ectopic Gene Expression
  • Endoribonucleases / metabolism*
  • Humans
  • Interferons / metabolism
  • Interferons / pharmacology
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Transport
  • Signal Transduction


  • Apoptosis Regulatory Proteins
  • Interferons
  • Protein Serine-Threonine Kinases
  • STK17A protein, human
  • JNK Mitogen-Activated Protein Kinases
  • Endoribonucleases
  • 2-5A-dependent ribonuclease
  • CASP3 protein, human
  • Caspase 3