Signal Transduction Mechanisms of Type I IFNs

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Our earlier work identified the signal transducer and activator of transcription (STAT)2 as a critical mediator in the promotion of type I interferon-induced apoptosis. This is an interesting observation as IFNs are the only cytokines known to activate STAT2. Our most recent work has identified a sensitive conserved region in STAT2 that following IFN stimulation can determine cell fate. In our cell line model, in response to IFN-alpha treatment, a mutation introduced in the Src-homology-region (SH2)-2 domain of STAT2 makes tumor cells undergo apoptosis that if they expressed the wild type form of STAT2, they are only growth arrested by this cytokine. Based on our studies, we concluded that this single amino acid change prolonged the physical interaction between STAT1 and STAT2. This alone allowed the STAT heterodimer to increase its duration in the nucleus while increasing the transcriptional levels of IFN-stimulated genes. These findings prompted us to examine carefully one STAT2 single nucleotide polymorphisms (SNP)detected in 12% in the human population. This SNP (M594I) is non-synonimous and found in the SH2 domain of STAT2. We measured its transcriptional function and consequently type I IFN biological responses against wild type STAT2. Our studies show that this SNP enhances the antiproliferative effects of type I IFNs. More interestingly, tumor cells known to be growth arrested by type IFNs, when they expressed this SNP became susceptible to the apoptotic effects of this cytokine. To establish an association between this SNP and IFN therapy, we analyzed a cohort of Hepatitis C patients who had received IFN treatment to control viral infection. Patients heterozygote for STAT2 M594I responded better to IFN therapy that those who were STAT2 homozygote. Collectively our findings strongly suggest that STAT2 is a critical component in the activation of apoptosis induced by type I IFNs and specific STAT2 mutations may be beneficial or counterproductive to a patient being treated with IFN.