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Signaling through the IFN type I receptor is mediated by assembly of the ISGF3 complex consisting of STAT1, STAT2 and IRF9. Whereas STAT1 is instrumentalized by many cytokines, STAT2 is specifically used by type I IFNs. Here, we report that the main regulatory mechanism of nuclear accumulation of STAT2 is nuclear export. We determined the kinetics of nucleocytoplasmic shuttling of STAT2 in living cells. In the absence of IFN, a virtually exclusive cytoplasmic localisation of STAT2 can be detected. Nevertheless, STAT2 is permanently and rapidly shuttling between the cytoplasm and the nucleus. The steady-state localization is explained by a very efficient nuclear export. Our studies indicate that at least two pathways (one of which is CRM1-dependent, the other not yet identified) are responsible for clearing the nucleus from STAT2. The constitutive nucleocytoplasmic shuttling of STAT2 does neither depend on the presence of IRF9 or STAT1, nor does it require tyrosine phosphorylation. Upon treatment with IFN type I, nuclear export of STAT2 is completely abolished in cells used within this study, whereas nuclear import is functioning. This explains the observed nuclear accumulation of STAT2. We have identified a region in the C-terminus of STAT2 that is essential for its almost exclusively cytoplasmic localization in the absence of IFN and responsible for CRM1-specific export. In comparative studies we show that nucleocytoplasmic shuttling of STAT2 is significantly different from that of STAT1. STAT1 is also shuttling in the absence of IFN, but the exchange rate in unstimulated cells is more than ten times lower. We further show that the latent STAT2 protein has stronger intrinsic nuclear-export activity than STAT1. Together, these observations lead to a model for IFN-type-I-induction in which the receptor-mediated heterodimerization overcomes the slow nuclear import of STAT1 and blocks the strong STAT2 export activity that leads to the accumulation of both signal transducers in the nucleus.

IFN-type-I-mediated signaling is regulated by modulation of STAT2 nuclear export