Transcriptional role of p53 in interferon-mediated antiviral immunity.
Tumor suppressor p53 is activated by several stimuli, including DNA damage and oncogenic stress. Previous studies (Takaoka, A., S. Hayakawa, H. Yanai, D. Stoiber, H. Negishi, H. Kikuchi, S. Sasaki, K. Imai, T. Shibue, K. Honda, and T. Taniguchi. 2003. Nature. 424:516-523) have shown that p53 is also induced in response to viral infections as a downstream transcriptional target of type I interferon (IFN) signaling. Moreover, many viruses, including SV40, human papillomavirus, Kaposi's sarcoma herpesvirus, adenoviruses, and even RNA viruses such as polioviruses, have evolved mechanisms designated to abrogate p53 responses. We describe a novel p53 function in the activation of the IFN pathway. We observed that infected mouse and human cells with functional p53 exhibited markedly decreased viral replication early after infection. This early inhibition of viral replication was mediated both in vitro and in vivo by a p53-dependent enhancement of IFN signaling, specifically the induction of genes containing IFN-stimulated response elements. Of note, p53 also contributed to an increase in IFN release from infected cells. We established that this p53-dependent enhancement of IFN signaling is dependent to a great extent on the ability of p53 to activate the transcription of IFN regulatory factor 9, a central component of the IFN-stimulated gene factor 3 complex. Our results demonstrate that p53 contributes to innate immunity by enhancing IFN-dependent antiviral activity independent of its functions as a proapoptotic and tumor suppressor gene.
Muñoz-Fontela
César
C
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
Macip
Salvador
S
Martínez-Sobrido
Luis
L
Brown
Lauren
L
Ashour
Joseph
J
García-Sastre
Adolfo
A
Lee
Sam W
SW
Aaronson
Stuart A
SA
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018390:Gene Targeting; D016158:Genes, p53; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics; D007372:Interferons / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D014158:Transcription, Genetic; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology* / Q000472:pathogenicity / Q000502:physiology; D014779:Virus Replication / Q000235:genetics / Q000276:immunology
C494227:IRF9 protein, human; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D049452:Green Fluorescent Proteins; D007372:Interferons