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Simian virus-40 infection inhibits DNA damage-induced enhancement of CD95 expression and function
Michael A Sheard1, Borivoj Vojtesek
1Laboratory of Apoptosis Research, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656 53 Brno, The Czech Republic. sheard@mou.cz
Abstract:
Many viruses are known to disarm or suppress the cell death machinery of infected cells. Apoptotic cell death can be activated by aggregation of the CD95 cell surface death receptor in sensitive cells, and in most insensitive cells treated with sensitizing agents such as interferon-gamma or inhibitors of protein synthesis. We show that, subsequent to sequestration and inactivation of the p53 tumour suppressor protein, SV40 abrogates p53-dependent, DNA damage-inducible up-regulation of CD95 surface expression. Loss of surface up-regulation of CD95 after sub-lethal mitomycin C treatment resulted in an impaired enhancement of both caspase-8 cleavage and apoptotic cell death following CD95 aggregation. We conclude that infection of human cells with SV40 virus strongly inhibits DNA damage-induced enhancement of CD95-mediated apoptosis.
Insights
Simian virus 40 (SV40) infection suppresses DNA damage-induced CD95 (also known as Fas) expression in human cells. This viral interference impairs CD95-mediated apoptosis, highlighting a novel viral immune evasion strategy.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- Viruses often evade host defenses by manipulating cellular processes, including programmed cell death (apoptosis).
- The CD95 (Fas) receptor pathway is a critical mediator of apoptosis, activated by receptor aggregation.
- Cellular stress, such as DNA damage, can sensitize cells to CD95-mediated apoptosis.
Purpose of the Study:
- To investigate the effect of Simian virus 40 (SV40) infection on DNA damage-induced CD95 expression and subsequent apoptosis.
- To determine the role of the p53 tumor suppressor protein in this process.
Main Methods:
- SV40 infection of human cells.
- Treatment with sub-lethal mitomycin C to induce DNA damage.
- Analysis of CD95 surface expression via flow cytometry.
- Assessment of caspase-8 cleavage and apoptotic cell death following CD95 aggregation.
Main Results:
- SV40 infection sequesters and inactivates the p53 tumor suppressor protein.
- SV40 abrogates the p53-dependent, DNA damage-induced upregulation of CD95 surface expression.
- Reduced CD95 surface expression leads to impaired caspase-8 cleavage and apoptotic cell death upon CD95 aggregation after DNA damage.
Conclusions:
- SV40 infection significantly inhibits the enhancement of CD95-mediated apoptosis induced by DNA damage in human cells.
- This inhibition is linked to SV40's suppression of p53 and subsequent downregulation of CD95 expression.
- SV40 employs this mechanism to evade host antiviral responses mediated by apoptosis.