Down-Regulation of p53 by Double-Stranded RNA Modulates the Antiviral Response

Abstract

p53 has been well characterized as a tumor suppressor gene, but its role in antiviral defense remains unclear. A recent report has demonstrated that p53 can be induced by interferons and is activated after vesicular stomatitis virus (VSV) infection. We observed that different nononcogenic viruses, including encephalomyocarditis virus (EMCV) and human parainfluenza virus type 3 (HPIV3), induced down-regulation of p53 in infected cells. Double-stranded RNA (dsRNA) and a mutant vaccinia virus lacking the dsRNA binding protein E3L can also induce this effect, indicating that dsRNA formed during viral infection is likely the trigger for down-regulation of p53. The mechanism of down-regulation of p53 by dsRNA relies on translation inhibition mediated by the PKR and RNase L pathways. In the absence of p53, the replication of both EMCV and HPIV3 was retarded, whereas, conversely, VSV replication was enhanced. Cell cycle analysis indicated that wild-type (WT) but not p53 knockout (KO) fibroblasts undergo an early-G 1 arrest following dsRNA treatment. Moreover, in WT cells the onset of dsRNA-induced apoptosis begins after p53 levels are down-regulated, whereas p53 KO cells, which lack the early-G 1 arrest, rapidly undergo apoptosis. Hence, our data suggest that the down-regulation of p53 facilitates apoptosis, thereby limiting viral replication.

Double-stranded RNA-dependent Protein Kinase Phosphorylation of the α-Subunit of Eukaryotic Translation Initiation Factor 2 Mediates Apoptosis

“…It has been proposed that PKR mediates apoptosis at the transcriptional level. For example, PKR signals through STAT1 and STAT3 (36,43,44), interferon regulatory factor 1 (IRF1) (16,45), IRF3 (46), p53 (17,47,48), and the IKK complex to regulate transcription during proinflammatory (16,17,40,45) and/or proapoptotic responses (12,40,45,49). PKR-dependent apoptosis was also associated with Fas-associated death domain (FADD)-mediated activation of caspase 8 (50,51) and up-regulation of Fas and Bax (18,52,53).…”

Single-stranded RNA viruses inactivate the transcriptional activity of p53 but induce NOXA-dependent apoptosis via post-translational modifications of IRF-1, IRF-3 and CREB

“…The role of p53 in virus-induced apoptosis remains controversial. Thus, the finding that vesicular stomatis virus (VSV) infection can activate the p53 protein (Takaoka et al, 2003) suggests that p53 may play a role in virus-induced apoptosis, whereas on the other hand, destabilization of the p53 reported during ssRNA virus infection suggests that p53 degradation may facilitate apoptosis induced by ssRNA viruses (Marques et al, 2005). Both viral dsRNA and viral DNA have been shown, however, to induce apoptosis by mechanisms independent of both IFNs and p53 (Weaver et al, 2001).…”

PKR , a p53 target gene, plays a crucial role in the tumor-suppressor function of p53

“…PKR is one of the best-characterized protein kinases and is involved both in IFN-mediated antiviral activity (18) and in IFNmediated anti-oncogenic activity (14,16). Recently, it also was found that PKR or viral dsRNA down-regulates p53 (19,20). Although the biological functions of PKR have been evaluated, it remains unclear whether the induction of PKR expression is exclusively dependent on type I IFN.…”