Abstract
SV40 large T-antigen (T-ag) has been known for decades to inactivate the tumor suppressor p53 by sequestration and additional mechanisms. Our present study revealed that the struggle between p53 and T-ag begins very early in the infection cycle. We found that p53 is activated early after SV40 infection and defends the host against the infection. Using live cell imaging and single cell analyses we found that p53 dynamics are variable among individual cells, with only a subset of cells activating p53 immediately after SV40 infection. This cell-to-cell variabilty had clear consequences on the outcome of the infection. None of the cells with elevated p53 at the beginning of the infection proceeded to express T-ag, suggesting a p53-dependent decision between abortive and productive infection. In addition, we show that artificial elevation of p53 levels prior to the infection reduces infection efficiency, supporting a role for p53 in defending against SV40. We further found that the p53-mediated host defense mechanism against SV40 is not facilitated by apoptosis nor via interferon-stimulated genes. Instead p53 binds to the viral DNA at the T-ag promoter region, prevents its transcriptional activation by Sp1, and halts the progress of the infection. These findings shed new light on the long studied struggle between SV40 T-ag and p53, as developed during virus-host coevolution. Our studies indicate that the fate of SV40 infection is determined as soon as the viral DNA enters the nucleus, before the onset of viral gene expression.
Highlights
We demonstrate that unlike Akt-1, p53 participates in host defense
Instead we revealed that p53 protects cells from SV40 infection by a new mechanism; it binds to the viral DNA when it enters the nucleus and interferes with the progress of infection by repressing T-ag transcription
Western blotting (Figure 1B) indicated that at 8 and 9 hours post infection level of total p53 rises significantly above the mock (p = 0.05 and 0.04 respectively) and it becomes phosphorylated at S392 (p = 0.02 and 0.002, respectively). p53 phosphorylation parallels an increase in the p53 protein, suggesting that SV40 infection leads to p53 induction as well as activation
Summary
P53 was originally discovered as a host protein associated with SV40 large T-antigen (T-ag) [1, 2]. T-ag is expressed soon after nuclear entry of the viral genome, during the early phase of the infection It regulates its own transcription by feedback inhibition [26] as well as the transition from early to late gene expression by activating the late promoter [27]. Protein phosphorylation arrays revealed that during the first 6 hours of SV40 infection the virus elicits concurrently two opposing pathways: pro-apoptotic, via PARP-1 and p53, and anti-apoptotic, via Akt-1 and Hsp70 [39]. Induction of apoptosis is a common host defense mechanism elicited by p53, viewed as an “altruistic” measure taken by infected cells to save the organism. Instead we revealed that p53 protects cells from SV40 infection by a new mechanism; it binds to the viral DNA when it enters the nucleus and interferes with the progress of infection by repressing T-ag transcription
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