Immunology Control of STAT Localization

Signal transducer and activator of transcription (STAT) proteins become tyrosine phosphorylated and dimerize before transport to the nucleus, where they activate the transcription of specific genes. What signals are required for STAT localization into the nucleus, however, has remained a mystery. Two reports provide some insight into this process. Begitt et al. showed that interferon- (IFN-)-stimulated cells treated with the nuclear export inhibitor leptomycin B (LMB) had reduced cytoplasmic levels of STAT1, suggesting that a nuclear export signal (NES) might exist in STAT1. Potential NES motifs were examined, and a functional motif (as measured by fluorescence assays) was identifed at residues 302 to 314, within the fourth helix of the STAT1 coiled-coil domain. Disruption of the NES, in a STAT1 mutant, strongly reduced cytoplasmic accumulation of mutant STAT1 in response to IFN treatment. Nuclear accumulation of STAT1 did not result in increased transcription of a STAT1-responsive reporter gene, implying that the transcription-enhancing integrity of accumulated STAT1 was diminished. Although it was not proven, it was suggested that the weakened transcriptional activity may be due to dephosphorylation of Tyr⁷⁰¹. Thus, after Tyr⁷⁰¹ phosphorylation and dimerization, STAT1 translocates to the nucleus to affect gene transcription, STAT1 becomes dephosphorylated, and an intact NES shuttles STAT1 back to the cytoplasm. Mowen and David also identify a NES motif in STAT1; however, it is located at residues 197 to 205. Nuclear translocation of STAT1 depended on the presence and kinase activity of Jak1. However, even when the EGF receptor phosphorylated STAT1, Jak1 was still necessary for the nuclear accumulation of STAT1. LMB-treated Jak1^-/- cells accumulated nuclear STAT1, suggesting that Jak1's role in STAT1 nuclear accumulation is most likely due to nuclear retention (and blocking export) rather than translocation to the nucleus. One caveat exists, that mutation of possible NES motifs may cryptically activate nonphysiological NESs.

Mowen, K., and David, M. (2000) Regulation of STAT1 nuclear export by Jak1. Mol. Cell. Biol. 20: 7273-7281. [Abstract] [Full Text]

Begitt, A., Meyer, T., van Rossum, M., and Vinkemeier, U. (2000) Nucleocytoplasmic translocation of Stat is regulated by a leucine-rich export signal in the coiled-coil domain. Proc. Natl. Acad. Sci. USA 97: 10418-10423. [Abstract] [Full Text]