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DNA-PK and ATM drive phosphorylation signatures that antagonistically regulate cytokine responses to herpesvirus
Joshua L Justice1, Tavis J Reed1, Brett Phelan1
1Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA.
Abstract:
The DNA-dependent protein kinase, DNA-PK, is an essential regulator of DNA damage repair. DNA-PK-driven phosphorylation events and the activated DNA damage response (DDR) pathways are also components of antiviral intrinsic and innate immune responses. Yet, it is not clear whether and how the DNA-PK response differs between these two forms of nucleic acid stress-DNA damage and DNA virus infection. Here, we define DNA-PK substrates and the signature cellular phosphoproteome response to DNA damage or infection with the nuclear-replicating DNA herpesvirus, HSV-1. We establish that DNA-PK negatively regulates the ataxia-telangiectasia-mutated (ATM) DDR kinase during viral infection. In turn, ATM blocks the binding of DNA-PK and the nuclear DNA sensor IFI16 to viral DNA, thereby inhibiting cytokine responses. However, following DNA damage, DNA-PK enhances ATM activity, which is required for IFN-β expression. These findings demonstrate that the DDR autoregulates cytokine expression through the opposing modulation of DDR kinases.
Insights
The DNA-dependent protein kinase (DNA-PK) response differs between DNA damage and viral infection. DNA-PK regulates DNA damage repair and antiviral immunity by modulating ATM kinase activity.
Area of Science:
- Molecular Biology
- Immunology
- Virology
Background:
- DNA-dependent protein kinase (DNA-PK) is crucial for DNA damage repair.
- DNA-PK and DNA damage response (DDR) pathways are involved in antiviral immunity.
- The distinct roles of DNA-PK in DNA damage versus viral infection remain unclear.
Purpose of the Study:
- To define DNA-PK substrates and cellular phosphoproteome responses to DNA damage and herpes simplex virus 1 (HSV-1) infection.
- To elucidate the differential regulation of DDR kinases by DNA-PK in response to distinct nucleic acid stresses.
Main Methods:
- Phosphoproteomic analysis of cells subjected to DNA damage or HSV-1 infection.
- Investigating the interplay between DNA-PK, ATM, and IFI16 in response to viral DNA and DNA damage.
Main Results:
- DNA-PK negatively regulates ATM during HSV-1 infection, inhibiting cytokine production.
- ATM activation by DNA-PK is essential for IFN-β expression following DNA damage.
- ATM blocks DNA-PK/IFI16 binding to viral DNA, suppressing antiviral cytokine responses.
Conclusions:
- The DNA damage response (DDR) autoregulates cytokine expression via differential modulation of DDR kinases.
- DNA-PK plays opposing roles in regulating ATM activity depending on the nature of the nucleic acid stress.
- Understanding these pathways is critical for both DNA repair and antiviral immunity research.
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