Potential contribution of tumor suppressor p53 in the host defense against hepatitis C virus

Abstract

Infection by hepatitis C virus (HCV) usually results into chronic hepatitis that can ultimately lead to cirrhosis and hepatocellular carcinoma. Type 1 interferons (IFN-␣/␤) constitute the primary cellular defense against viral infection including HCV. IFN binding to their receptors activates associated Jak1 and Tyk2 kinases, which ultimately leads to phosphorylation and assembly of a signal transducer and activator of transcription protein (STAT)1-STAT2-interferon regulatory factor (IRF)9 trimetric complex called interferonstimulated gene factor 3 that translocates into the nucleus and binds to the interferonstimulated response elements (ISRE), leading to transcriptional induction of several antiviral genes, including double-stranded RNA-activated protein kinase (PKR), 2 ,5 -oligoadenylate synthetase (OAS), and myxovirus resistance protein A (MxA). Understanding the mechanisms of how the virus evades this cellular innate defense and establishes a chronic infection is the key for the development of better therapeutics against HCV infection. Here, we demonstrate that p53 could have a crucial role in the cellular innate defense against HCV. We observed significantly higher levels of HCV RNA replication and viral protein expression in the Huh7 cells when their p53 expressions were knocked down. Moreover, IFN treatment was less effective in inhibiting the HCV RNA replication in the p53-knocked-down (p53kd) Huh7 cells. In fact, the activation of the ISRE and the induction of ISGs were significantly attenuated in the p53kd Huh7 cells and p53 was found to directly interact with IRF9. Conclusion: These observations underscore the potential contributions of the tumor suppressor p53 in cellular antiviral immunity against HCV with possible therapeutic implications.

The Codon 72 Polymorphism of p53 Regulates Interaction with NF-κB and Transactivation of Genes Involved in Immunity and Inflammation

“…The role of p53 in innate immunity and the inflammatory response is now well established (6,28,44) and, importantly, is evolutionarily conserved (11). Whereas the impact of the codon 72 polymorphism on cancer risk appears to be minor, there are compelling examples in the literature of an effect of this polymorphism on diseases associated with inflammation.…”

“…The transcription of the p53 gene is controlled by type I interferon (IFN) signaling (44), and the induction of p53 participates in the host defense against viral infection (6,28). p53 also interacts with interferon regulatory factor 9 (IRF9) to enhance IFN signaling (6).…”

“…The transcription of the p53 gene is controlled by type I interferon (IFN) signaling (44), and the induction of p53 participates in the host defense against viral infection (6,28). p53 also interacts with interferon regulatory factor 9 (IRF9) to enhance IFN signaling (6). Additionally, p53 regulates the transcription of several cytokines and chemokines involved in innate immunity; this activity of p53 is believed to contribute to the ability of the immune system to eliminate senescent cells (56).…”

Stabilization of p53 in Influenza A Virus-infected Cells Is Associated with Compromised MDM2-mediated Ubiquitination of p53

“…Besides its well established role in protection against the development of cancer, p53 has recently been implicated in host antiviral defense (15)(16)(17)(18). In response to IAV infection, p53 is accumulated and activated, and consequently transactivates its target genes responsible for regulating apoptosis and the innate immune response (10,11).…”

BIRC6 promotes hepatocellular carcinogenesis: Interaction of BIRC6 with p53 facilitating p53 degradation

“…In hepatoma cells, the mutated p53 still exhibits its transactivation activity as indicated by fact that the tumor suppressor p53 in Huh-7 cells is functionally intact despite the Y220C mutation. 38 Huh-7 cells are known to maintain an effective p53 transactivation activity comparable to that of Chang liver cells and HepG2 cells, both of which contain wild-type p53. 39,40 On the other hand, besides transcription activities the mutant p53 also executes nontranscription activities.…”