Cytokine-receptor complexes as chaperones for nuclear translocation of signal transducers

A variety of ligands that include interleukins, interferons, and growth hormones activate STAT transcriptions factors. When activated, STATs are translocated to the nucleus apparently through the well described importin/Ran system where they activate target genes. Molecules utilizing this nuclear import system require specific nuclear localization sequences (NLSs). Paradoxically, such NLSs are not identifiable on STATs, raising the question of how they are imported into the nucleus. Surprisingly, most ligands and/or receptors that signal through STATs contain putative NLSs, and where examined either ligand or receptor undergo nuclear translocation. We hypothesize that these ligands and/or their receptors serve as chaperones in the nuclear translocation of STATs, and that they may be directly involved in signal transduction. Using IFN gamma as a model system we provide a possible mechanism for how this direct role is fulfilled. A C-terminal domain of IFN gamma has been identified that contains a functional NLS. Besides the fact that this domain, and the NLS in particular, is crucial for the biological properties of IFN gamma, a peptide encompassing this domain is sufficient to induce an antiviral state. Moreover, this domain interacts exclusively with an internal cytoplasmic domain of a subunit of the receptor complex in a region that is directly involved in the recruitment and activation of the elements of the JAK/STAT pathway. We suggest that this novel mode of receptor recognition and activation may be a driving force for nuclear translocation of molecules like STATs that are associated with the ligand-receptor complex.