Murine cytomegalovirus IE3-dependent transcription is required for DAI/ZBP1-mediated necroptosis
Haripriya Sridharan1, Katherine B Ragan1, Hongyan Guo2
1Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, USA.
Abstract:
DNA-dependent activator of interferon regulatory factors/Z-DNA binding protein 1 (DAI/ZBP1) is a crucial sensor of necroptotic cell death induced by murine cytomegalovirus (MCMV) in its natural host. Here, we show that viral capsid transport to the nucleus and subsequent viral IE3-dependent early transcription are required for necroptosis. Necroptosis induction does not depend on input virion DNA or newly synthesized viral DNA A putative RNA-binding domain of DAI/ZBP1, Zα2, is required to sense virus and trigger necroptosis. Thus, MCMV IE3-dependent transcription from the viral genome plays a crucial role in activating DAI/ZBP1-dependent necroptosis. This implicates RNA transcripts generated by a large double-stranded DNA virus as a biologically relevant ligand for DAI/ZBP1 during natural viral infection.
Insights
Murine cytomegalovirus (MCMV) triggers necroptosis via DNA-dependent activator of interferon regulatory factors/Z-DNA binding protein 1 (DAI/ZBP1). Viral transcription, not viral DNA, activates DAI/ZBP1 sensing during MCMV infection.
Area of Science:
- Virology
- Immunology
- Cell Death Research
Background:
- DNA-dependent activator of interferon regulatory factors/Z-DNA binding protein 1 (DAI/ZBP1) is a key sensor for necroptotic cell death.
- Murine cytomegalovirus (MCMV) naturally induces necroptosis in its host via DAI/ZBP1.
- Understanding the precise triggers for DAI/ZBP1 activation during MCMV infection is crucial.
Purpose of the Study:
- To elucidate the specific viral events required for MCMV-induced necroptosis.
- To determine the role of viral DNA and transcription in activating DAI/ZBP1.
- To identify the molecular mechanism by which DAI/ZBP1 senses MCMV.
Main Methods:
- Investigated the requirement of viral capsid transport and early transcription for necroptosis.
- Assessed the role of input virion DNA and newly synthesized viral DNA in necroptosis induction.
- Utilized a putative RNA-binding domain (Zα2) of DAI/ZBP1 to understand its sensing function.
Main Results:
- Viral capsid transport to the nucleus and IE3-dependent early transcription are essential for MCMV-induced necroptosis.
- Necroptosis induction is independent of both input virion DNA and newly synthesized viral DNA.
- The Zα2 RNA-binding domain of DAI/ZBP1 is necessary for sensing the virus and initiating necroptosis.
Conclusions:
- MCMV IE3-dependent transcription from the viral genome is critical for activating DAI/ZBP1-mediated necroptosis.
- RNA transcripts from MCMV serve as biologically relevant ligands for DAI/ZBP1 during natural infection.
- This study reveals a novel mechanism of viral sensing and cell death induction involving viral RNA.
