PARP-1 mediated cell death is directly activated by ZIKV infection
Gang Xu1, Shihua Li2, Xinyuan Liu3
1Guangdong Key Laboratory for Diagnosis and Treatment of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, 518112, China.
Abstract:
Zika virus (ZIKV) has emerged as a severe health threat due to its association with microcephaly. It has been reported that the strong cytopathic effects, including cell-cycle arrest and cell death are responsible for the nervous system disease. However, the mechanisms by which ZIKV infection induced cell death were largely unknown. Here, we reported that cell death is readily detected after ZIKV infection as indicated by PI staining and the reduction of cell viability. Importantly, cell death can be induced by overexpression of ZIKV NS3 protein alone but not the other non-structure proteins. Mass spectrometry analysis revealed that NS3 bond to and activated PARP-1. In agreement with these observations, we found that PARP-1 was massively activated during ZIKV infection and the intracellular ATP and NAD+ concentrations rapidly declined. Finally, PARP-1 knockdown simultaneously restrained ZIKV infection-induced cell death and ablated host restriction of virus infection. Our finding indicates that PARP-1 activation is an important cellular event during ZIKV infection, which contributes to the cell death.
Insights
Zika virus (ZIKV) infection triggers cell death by activating PARP-1, a key protein. This activation is crucial for ZIKV-induced cell death and viral replication, offering a potential therapeutic target.
Area of Science:
- Virology
- Molecular Biology
- Cellular Biology
Background:
- Zika virus (ZIKV) poses a significant public health risk, linked to severe neurological conditions like microcephaly.
- While ZIKV's cytopathic effects, including cell death, are known to cause nervous system damage, the underlying mechanisms remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms by which Zika virus infection induces cell death.
- To investigate the role of specific ZIKV proteins in triggering cellular demise.
Main Methods:
- Assessed ZIKV-induced cell death using Propidium Iodide (PI) staining and cell viability assays.
- Utilized mass spectrometry to identify ZIKV protein interactions with host factors.
- Examined the impact of Poly (ADP-ribose) polymerase-1 (PARP-1) modulation on ZIKV infection and cell death.
Main Results:
- Zika virus infection demonstrably induces cell death, confirmed by reduced cell viability and PI staining.
- Overexpression of the ZIKV NS3 protein alone was sufficient to induce cell death.
- Mass spectrometry identified NS3 binding and activation of PARP-1, leading to rapid depletion of intracellular ATP and NAD+.
- PARP-1 activation was significantly elevated during ZIKV infection.
- Knockdown of PARP-1 suppressed ZIKV-induced cell death and reduced the host's ability to restrict viral infection.
Conclusions:
- PARP-1 activation is a critical cellular event during Zika virus infection.
- NS3-mediated PARP-1 activation contributes significantly to ZIKV-induced cell death.
- Targeting PARP-1 may represent a novel therapeutic strategy against ZIKV.
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