STAT dynamics
Introduction
Signal transducers and activators of transcription (STAT) possess the ability to both sense environmental cues and to transmit those cues to regulate specific gene expression. The founding members of this family, STAT1 and STAT2, were identified as latent DNA binding factors activated in response to type I interferons (IFNs)[1], [2]. Following IFN binding to cell surface receptors, the receptor-associated Janus kinases phosphorylate STATs on a specific tyrosine residue [3], [4], [5], [6], [7], [8]. Tyrosine phosphorylation induces a conformational change that generates STAT dimers via reciprocal phosphotyrosine and SH2 domain interaction [9], [10], [11]. The dimer conformation confers their ability to recognize specific DNA targets in the promoters of responsive genes, and the products of these genes contribute to the biological effects of IFNs on viral resistance, proliferation, and immune cell activation [12], [13], [14], [15].
STAT-mediated gene expression can have dramatic effects on cellular function, and for this reason it is not surprising that STAT activity is regulated by various means including receptor activated Janus kinases, cytoplasmic and nuclear tyrosine phosphatases, protein inhibitors of activated STATs (PIAS), and suppressors of cytokine signaling (SOCS) [16], [17], [18]. To affect gene transcription the STATs must gain access to the nucleus, and consequently nuclear localization is yet another mechanism of STAT regulation [19], [20]. Proteins as large as the STATs are restricted from passive diffusion into the nucleus, and so transport must be facilitated. Transport is an active energy-requiring process usually mediated by association with soluble transporters. Since nuclear trafficking has a significant impact on STAT function, understanding the mechanisms that regulate STAT localization should provide information valuable to enhance or prevent their action.
Section snippets
Properties of STAT molecules
Seven mammalian STAT genes have been identified, and although the encoded proteins share many properties, they respond uniquely to specific stimuli and confer distinct biological responses. The STATs have a similar structural arrangement of functional motifs (Fig. 1) [12]. These include an amino terminus that plays a role in dimerization, a coiled coil domain that can be involved in interactions with other proteins, a central DNA binding domain (DBD), a Src homology 2 (SH2) domain, a conserved
Nuclear trafficking
The genomic information of eukaryotic cells is partitioned from the cytoplasm by a membrane bound nucleus. The movement of molecules in and out of the nucleus occurs through discrete passageways known as nuclear pore complexes (NPCs) that span the nuclear membrane [34], [35]. Small molecules can freely diffuse through the NPCs, however the movement of large molecules is restricted. To pass through the NPC, macromolecules must be able to directly interact with the proteins that comprise the NPC,
STAT1 dynamics
Regulated cellular localization can function as a molecular switch to turn on or turn off a signal. Similarly, the regulated ability to bind DNA can serve as a molecular switch to turn on or turn off gene expression. The tyrosine phosphorylation of STAT1 activates both of these molecular switches. The dimer that is generated by reciprocal phosphotyrosine-SH2 domain interaction between STAT1 monomers gains the ability to recognize a specific importin-α adapter, and to recognize a specific DNA
STAT2 dynamics
STAT2 is tyrosine phosphorylated in response to type I IFNs, and it dimerizes with phosphorylated STAT1 to form heterodimers that are actively imported to the nucleus. STAT2 is distinct among the STATs in its ability to bind to IRF-9 constitutively, and this property suggested that STAT2 localization may be regulated differently from STAT1 [25]. Evidence now indicates that the unphosphorylated STAT2 molecule constitutively shuttles in and out of the nucleus, the import mediated by IRF-9 and the
Summary
A successful innate immune response to viral infection requires the action of IFNs and the induced expression of genes by ISGF3 (STAT1:STAT2:IRF-9) and GAF (STAT1:STAT1). The physiological significance of these transcription factors is clearly evident in animals lacking STAT1 or STAT2, as these deficient animals succumb to infection [59], [60], [61]. It is therefore not unexpected that the STATs are regulated by various mechanisms including tyrosine phosphorylation by JAKs, inhibition
Acknowledgements
This review could not have been written without the thoughtful and skillful contributions of current and past laboratory members. Thank you all. Grant support from N.I.H. to N.C.R. is gratefully acknowledged (PO1CA2814 and RO1 CA122910).
Nancy C. Reich, Ph.D. is a Professor of Molecular Genetics and Microbiology at Stony Brook University, New York. She received her Ph.D. from Stony Brook University studying viral-host interactions and the p53 tumor suppressor with Dr. Arnold J. Levine. Subsequently she joined Dr. James. E. Darnell, Jr. at The Rockefeller University as a Postdoctoral Associate and entered the field of interferon research. Her research is funded by N.I.H. and she has served on numerous N.I.H. advisory panels. She
References (61)
A transcription factor with SH2 and SH3 domains is directly activated by an interferon alpha-induced cytoplasmic protein tyrosine kinase(s)
Cell
(1992)- et al.
Structural bases of unphosphorylated STAT1 association and receptor binding
Mol Cell
(2005) - et al.
Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA
Cell
(1998) - et al.
Complex modulation of cell type-specific signaling in response to type I interferons
Immunity
(2006) The Stat family in cytokine signaling
Curr Opin Cell Biol
(2001)- et al.
Inhibitors of cytokine signal transduction
J Biol Chem
(2004) - et al.
STAT2 nuclear trafficking
J Biol Chem
(2004) - et al.
Distinct STAT structure promotes interaction of STAT2 with the p48 subunit of the interferon-alpha-stimulated transcription factor ISGF3
J Biol Chem
(1997) - et al.
The nuclear pore complex as a transport machine
J Biol Chem
(2001) - et al.
Karyopherins and nuclear import
Curr Opin Struct Biol
(2001)
Classical nuclear localization signals: definition, function, and interaction with importin alpha
J Biol Chem
Leptomycin B inhibition of signal-mediated nuclear export by direct binding to CRM1
Exp Cell Res
Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions
Cell
Importin alpha nuclear localization signal binding sites for STAT1, STAT2, and influenza A virus nucleoprotein
J Biol Chem
Arginine/lysine-rich nuclear localization signals mediate interactions between dimeric STATs and importin alpha 5
J Biol Chem
Immune response in Stat2 knockout mice
Immunity
Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease
Cell
Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway
Cell
The proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction
Proc Natl Acad Sci USA
Proteins of transcription factor ISGF-3: one gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha
Proc Natl Acad Sci USA
Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor [see comments]
Science
Activation of the protein tyrosine kinase tyk2 by interferon alpha/beta
Eur J Biochem
Ligand-induced IFN gamma receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91)
Embo J
A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma [see comments]
Science
Tyrosine phosphorylation is required for activation of an alpha interferon-stimulated transcription factor
Proc Natl Acad Sci USA
Three-dimensional structure of the Stat3beta homodimer bound to DNA
Nature
Stats: transcriptional control and biological impact
Nat Rev Mol Cell Biol
Jaks and STATs: biological implications
Annu Rev Immunol
Identification of a nuclear Stat1 protein tyrosine phosphatase
Mol Cell Biol
Regulation of cytokine signaling pathways by PIAS proteins
Cell Res
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2017, Redox BiologyCitation Excerpt :Further studies are needed to assess the participation of PTP1B, the differential responses of STAT1 and STAT3 phosphorylation to LA and their redox regulation in neuronal cells. Tyrosine phosphorylation leads to STAT1 dimerization, which reveals a nuclear localization signal that is recognized by nuclear specific carriers (importins) for subsequent nuclear import [47–49]. While STAT3 tyrosine phosphorylation facilitates the dimer nuclear/cytoplasmic shuttling [57], STAT3 nuclear translocation can also occur independently of tyrosine phosphorylation [49,58].
Nancy C. Reich, Ph.D. is a Professor of Molecular Genetics and Microbiology at Stony Brook University, New York. She received her Ph.D. from Stony Brook University studying viral-host interactions and the p53 tumor suppressor with Dr. Arnold J. Levine. Subsequently she joined Dr. James. E. Darnell, Jr. at The Rockefeller University as a Postdoctoral Associate and entered the field of interferon research. Her research is funded by N.I.H. and she has served on numerous N.I.H. advisory panels. She has been an active member in ISICR and was the 2005 co-recipient of the Milstein Award for exceptional contributions to this field. Her research interests have long centered on innate immunity and the response of cells to viral infections. Some of her professional highlights include discovery of a novel DNA binding factor activated in response to viral infection identified as IRF-3; discovery of tyrosine phosphorylation in the activation of transcription factors STAT1 and STAT2; discovery of the ability of Ras to activate STAT3 indirectly; development of a transgenic JAK/STAT reporter system in Drosophila that can be used to screen for pathway modulators; and elucidation of the mechanisms that distinguish nuclear trafficking of STATs.