Type I interferons (IFN-1) are best known for their role in innate immunity, but they are also involved in immunomodulation, proliferation, cancer surveillance, and the regulation of the adaptive immune response. How does the interaction of a cytokine with its receptors promote such diverse activities? To answer this question, I generated knockout (KO) HeLa cell lines and learned how these KOs affect different activities. The deletion of either STAT1 or STAT2 alone reduced, but did not eliminate IFN-1 induced activities. Conversely, the deletion of both completely abrogated any IFN-1 activity. So did the double STAT2-IRF1 KO, and a knockdown of IRF9 on background of STAT1 KO, suggesting the GAS pathway and the STAT2-IRF9 dimer as complimentary pathways to STAT1-STAT2. Interestingly, deletion of any of the mentioned components had no effect on the phosporylation of any of the other STATs including STAT3 and STAT6. To directly asses the importance of STAT3 in the system, I generates its KO, which had no effect on IFN-1 activation. Those evidence suggest that IFN-1 induced signaling goes only through STAT1 and STAT2, although not both are required.
