STAT dynamics

Abstract

The ability of transcription factors to gain entrance to the nucleus is critical to their role in gene expression. Signal transducers and activators of transcription (STATs) are latent DNA binding factors activated by specific tyrosine phosphorylation. There are seven mammalian STAT genes encoding proteins that display constitutive nuclear localization and/or conditional nuclear localization. This review will focus on STAT1 and STAT2 that are activated in response to interferon and exhibit conditional nuclear localization. The dynamic redistribution of STAT1 and STAT2 between the cytoplasm and the nucleus is coordinate with their gain of ability to bind DNA.

Figure 1

STAT cellular redistribution. Top) Schematic consensus of STAT domain arrangement with coiled coil domain (CC), DNA binding domain (DBD), Src homology domain 2 (SH2), tyrosine target of phosphorylation (Yp), and transcriptional activation domain (TAD). Bottom) Fluorescence microscopy of cells expressing STAT1-GFP or STAT2-GFP. Cells were untreated (−) or treated with 1000U/ml IFNα for 1 hour (+). Figure is modified from previous publications (24, 45).

Figure 2

Schematic of JAK/STAT signal pathways stimulated by IFNs. Left) Type I IFNs (primarily α/β) bind to the IFNAR activating JAK1 and TYK2. The JAKs phosphorylate the receptors and recruited STAT1 and STAT2. The STATs heterodimerize and with IRF-9 form ISGF3 to bind to the ISRE in target genes. STAT1 homodimers are also formed and can bind to the GAS. Right) Type II IFN (γ) binds to a distinct IFNGR activating JAK1 and JAK2. These JAKs phosphorylate sites on the receptor and the recruited STAT1. STAT1 factors dimerize and gain the ability to bind to the GAS in target genes.

Figure 3

Illustration of nuclear trafficking mediated by soluble transporters. Nuclear import can be mediated by the importin-α/importinβ1 heterodimer via recognition of the NLS in proteins. Nuclear export can be mediated by the CRM1 exportin and recognition of the NES in proteins. Leptomycin B (LMB) can specifically inhibit CRM1-mediated export.

Figure 4

Conceptual diagram of STAT1 dynamics. STAT1 resides primarily in the cytoplasm prior to tyrosine phosphorylation, but following phosphorylation the STAT1 dimer is recognized by importin-α5. The active STAT1 dimer is imported into the nucleus and binds specific DNA targets. Bound to DNA the NES is masked, but following dissociation from DNA the NES is accessible to CRM1 and the protein is exported from the nucleus. The location of the NES and sequences required for NLS function are indicated in the DNA binding domain.

Figure 5

Conceptual diagram of STAT2 dynamics. Unphosphorylated STAT2 in association with IRF-9 is imported into the nucleus via the NLS in IRF-9, however the strong constitutive NES in the carboxyl terminus of STAT2 redistributes the unphosphorylated STAT2 back to the cytoplasm. The unphosphorylated STAT2 is thereby constitutively shuttling in and out of the nucleus. Following tyrosine phosphorylation, STAT2 heterodimerizes with STAT1 and this leads to the gain of a NLS that is recognized by importin-α5 and the gain of an ability to bind DNA. Following dissociation from DNA STAT2 is actively exported from the nucleus.