Phosphorylation-induced dimerization of interferon regulatory factor 7 unmasks DNA binding and a bipartite transactivation domain

Interferon regulatory factor 7 (IRF7) is an interferon (IPN)-inducible tran scription factor required for activation of a subset of IFN-alpha genes tha t are expressed with delayed kinetics following viral infection. IRF7 is sy nthesized as a latent protein and is posttranslationally modified by protei n phosphorylation in infected cells. Phosphorylation required a carboxyl-te rminal regulatory domain that controlled the retention of the active protei n exclusively in the nucleus, as well as its binding to specific DNA target sequences, multimerization, and ability to induce target gene expression. Transcriptional activation by IRF7 mapped to two distinct regions, both of which were required for full activity, while all functions were masked in l atent IRF7 by an autoinhibitory domain mapping to an internal region. A con ditionally active form of IRF7 was constructed by fusing IRF7 with the liga nd-binding and dimerization domain of estrogen receptor (ER). Hormone-depen dent dimerization of chimeric IRF7-ER stimulated DNA binding and transcript ional transactivation of endogenous target genes. These studies demonstrate the regulation of IRF7 activity by phosphorylation-dependent allosteric ch anges that result in dimerization and that facilitate nuclear retention, de repress transactivation, and allow specific DNA binding.