A Single Residue Modulates Tyrosine Dephosphorylation, Oligomerization, and Nuclear Accumulation of Stat Transcription Factors

Meyer, Thomas; Hendry, Lisa; Begitt, Andreas; John, Susan; Vinkemeier, Uwe

doi:10.1074/jbc.m400766200

Cited by 70 publications

(86 citation statements)

References 45 publications

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“…At present, it is not known whether these modifications control permeability through the nuclear pore of STATs other than STAT1, but export of C-terminally truncated STAT3 and STAT5 is slow and comparable to truncated STAT1 (4). Alternative splicing has also been implicated in tyrosine phosphorylation and the stability of the STAT molecule, although the molecular mechanisms are incompletely understood (33,44,46,47). Of note, serine phosphorylation of an unrelated site of STATa from Dictyostelium increases nuclear export, again in the absence of NES activity of the phosphorylated peptide (48).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Export Determines the Cytokine Sensitivity of STAT Transcription Factors

Lödige

Marg

Wiesner

et al. 2005

Journal of Biological Chemistry

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Cytokine-dependent gene activation critically depends upon the tyrosine phosphorylation (activation) of STAT transcription factors at membrane-bound cytokine receptors. The extent of STAT activation and hence the specificity of signaling is primarily determined by structural complementarity between the SH2 domain of the STATs and the tyrosine-phosphorylated receptor chains. Here, we identified constitutive nucleocytoplasmic shuttling as another mechanism that controls the differential activation of STAT transcription factors. Our analysis of nucleocytoplasmic cycling of STAT1 revealed that the expression of the alternatively spliced transactivation domain and its signal-dependent serine phosphorylation maximized the rate of nuclear export. Export modulation occurred independently of retention factors or the export receptor CRM1, and was observed both before and during stimulation of cells with cytokines. Our data indicated a dual role for the transactivation domain. It enhanced the nuclear retention of activated STAT1, but had the opposite effect on inactivated molecules. Accordingly, and despite their identical receptor recognition, the STAT1 splice variants differed strongly in the amplitude of tyrosine phosphorylation and in the duration of the cytokine signal. Thus, regulated nuclear export determined the cytokine sensitivity of the shuttling STAT1 transcription factors by controlling their availability at the receptor kinase complex. Cytokines such as interferon ␥ (IFN␥)2 engage the Janus kinase/signal transducer and activator of transcription (STAT) signaling pathway during inflammatory and immune responses (1). Activation of this pathway by IFN␥ induces the phosphorylation of an intracellular tyrosine residue in the ␣-chain of the IFN␥ receptor. This, in turn, creates the docking site specifically for the SH2 domain of STAT1. Subsequently, phosphorylation of residue tyrosine 701 of STAT1 triggers the dissociation from the receptor and SH2 domain-mediated STAT1 homodimerization that transforms the latent transcription factor into a high affinity DNA-binding protein (2). The STATs are nucleocytoplasmic shuttling proteins that make use of both carrier-independent and carrier-mediated translocation mechanisms (3) (Fig. 1A). Before tyrosine phosphorylation, direct binding to proteins of the nuclear pore (nucleoporins) allows carrier-independent transportation of STAT1 (4). Additionally, the exportin CRM1 supports nuclear export to a minor extent (4). Tyrosine-phosphorylated STAT1 dimers, on the other hand, are barred from further carrier-independent nucleocytoplasmic exchange (4). Instead, association with importin ␣5 and importin ␤ is necessary for continued nuclear import (5, 6). However, tyrosine phosphorylation triggers the nuclear retention of the shuttling STAT1, which is kept in the nucleus until tyrosine dephosphorylation takes place. The inhibition of the dephosphorylation reaction afforded by DNA binding suffices to bring about the easily observable accumulation of STAT molecules in the nucleus (7). ...

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Section: Discussionmentioning

confidence: 99%

Nuclear Export Determines the Cytokine Sensitivity of STAT Transcription Factors

Lödige

Marg

Wiesner

et al. 2005

Journal of Biological Chemistry

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“…Lymphocytes of Fl-Stat5 -/-mice still express partly functional NH2-terminal truncated proteins (H. N. and J. K., unpublished results) and these STAT5 isoforms, which are also found in normal cells, are sufficient to ensure normal intrathymic T cell development regulated by IL-7, but they are insufficient for IL-15 signaling 25,43 . The N-terminal region of STAT5 has been implicated in both positive and negative regulatory functions of nuclear STAT5, including nuclear retention, protein dephosphorylation, oligomerization, and co-factor recruitment 48 . Among these properties, STAT5 tetramerization has emerged as a central feature of optimal STAT5 activity, especially critical for stimulating the expression of genes with suboptimal STAT5 consensus binding motifs 49 .…”

Section: Discussionmentioning

confidence: 99%

Interleukin 15 controls the generation of the restricted T cell receptor repertoire of γδ intestinal intraepithelial lymphocytes

2005

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AbstractγδT cells are prevalent in the mucosal epithelia and are postulated to act as sentries to maintain tissue integrity. What these γδT cells recognize is poorly defined, but based on the restricted T cell receptor (TCR) repertoire, the notion that they are selected by self-antigens of low complexity has been widely disseminated. We present data demonstrating that generation of the restricted TCR Vγ gene repertoire of intestinal intraepithelial lymphocytes is regulated by IL-15, which induces Vγ gene segmentspecific local chromatin modifications and enhanced accessibility conducive for subsequent targeted gene rearrangement. This cytokine-directed tissue-specific TCR repertoire formation likely reflects distinct TCR repertoire selection criteria for γδ and αβT cell lineages adopted for different antigen recognition strategies.Intestinal intraepithelial lymphocytes (i-IELs) found within the intestinal epithelial layer are an essential component of mucosal immunity. Similar to T cell subsets in other lymphoid tissues, i-IELs are composed of two T cell types, αβ and γδT cells. In contrast to other tissues, however, γδT cells are prevalent in the mucosal epithelia of most vertebrates and are thought to be a major source of secreted factors necessary for the maintenance of tissue integrity subsequent to infection, transformation, or cell injury 1-3 .Despite the long history of i-IELs, their origin and ligand specificity remain uncertain. Earlier work has indicated that αβ i-IELs originate exclusively from the thymus in normal mice 4 , but whether γδ i-IELs are subject to similar developmental constraints is unclear. The majority of human and mouse γδ i-IELs express the homodimeric αα form of the CD8 coreceptor and exhibit restricted Variable (V) γ and V δ gene usage. In C57BL/6 (B6) mice, for example, V γ 5 expressing cells constitute the predominant i-IEL population in the small intestine [5][6][7] . Mouse strain-specific preferential usage of Tcrg and Tcrd genes among i-IELs arises from complex molecular and cellular controls with evidence for genetic linkage to the Tcrg, Tcrd and H2 loci 6,8,9 , but the exact mechanism is unknown. Two non-mutually exclusive mechanistic processes can be considered to account for the restricted TCR gene usage: cellular selection and programmed TCR gene rearrangement. A hallmark of adaptive immunity is the cellular selection process geared toward forming a population of cells with antigen receptor repertoires that can recognize the entire external universe of antigens. This selection pressure acts on immature cell subsets expressing randomly generated clonal antigen receptors. Although the TCR-driven selection shaping the αβTCR repertoire of conventional αβT cells constitutes a fundamental theme in immunology, whether a similar process is needed for γδT cell development, and specifically for γδ i-IELs, remains a matter of debate [10][11][12] .

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“…The N-terminal region of the STAT proteins, which comprises approximately 130 residues that assemble into 8 α-helices separated by short linkers (32)(33)(34), has been implicated in diverse functions including STAT activation, deactivation and target gene expression (35)(36)(37). For example, the N-domain of STAT4 is required for cytokine-responsive activation via tyrosine phosphorylation (36,38) by mediating the formation of STAT4 oligomers in the cytoplasm (35).…”

Section: Introductionmentioning

confidence: 99%

“…For example, the N-domain of STAT4 is required for cytokine-responsive activation via tyrosine phosphorylation (36,38) by mediating the formation of STAT4 oligomers in the cytoplasm (35). By contrast, the N-domains of STAT1 and STAT5 control the kinetics of STAT deactivation; for STAT1 this is regulated by N-domain-dependent recruitment of the nuclear tyrosine phosphatase TC45 (37). Isolated STAT N-domains show potent homotypic interactions (35).…”

Section: Introductionmentioning

confidence: 99%

IL-6 signaling via the STAT3/SOCS3 pathway: Functional Analysis of the Conserved STAT3 N-domain

et al. 2006

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The conserved N-domain of the STAT proteins has been implicated in several activities crucial to cytokine signaling including receptor recruitment and STAT activation, cooperative DNA binding and STAT-dependent gene expression. We evaluated the role of the STAT3 N-domain in the IL-6 signal transduction pathway leading to Socs3 gene expression, an essential mechanism that controls the quality and magnitude of IL-6-dependent transcriptional responses. Based on the model for STAT N-domain function in cooperative gene expression and the presence of tandem STAT binding motifs in the murine Socs3 promoter, we anticipated that stabilizing interactions between adjacent STAT3 dimers via N-domain sequences might be essential for Socs3 gene expression. This was underscored by the tight conservation in the location and sequence of the tandem STAT binding sites between the murine and human Socs3 promoters. Using reconstitution into Stat3−/− mouse embryonic fibroblasts (Stat3−/− MEFs), we find that a STAT3 N-domain deletion mutant (Δ133STAT3) is activated by tyrosine phosphorylation in response to IL-6 and then undergoes dephosphorylation with kinetics similar to full-length STAT3. These results highlight important differences compared to other STATs where the N-domain has been shown to mediate activation (STAT4) or dephosphorylation (STAT1). STAT3 binds predominantly to a single STAT consensus site in the Socs3 promoter, despite the presence of an adjacent STAT motif. Significantly, Δ133STAT3 stimulates expression of the endogenous Socs3 gene in Stat3−/− MEFs upon IL-6 treatment with an activity similar to reconstituted STAT3, demonstrating that the N-domain is dispensable for Socs3 gene expression. We propose that the Socs3 gene in its chromosomal context is activated by the IL-6/ STAT3 pathway independent of STAT3 N-domain sequences.

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A Single Residue Modulates Tyrosine Dephosphorylation, Oligomerization, and Nuclear Accumulation of Stat Transcription Factors

Cited by 70 publications

References 45 publications

Nuclear Export Determines the Cytokine Sensitivity of STAT Transcription Factors

Nuclear Export Determines the Cytokine Sensitivity of STAT Transcription Factors

Interleukin 15 controls the generation of the restricted T cell receptor repertoire of γδ intestinal intraepithelial lymphocytes

IL-6 signaling via the STAT3/SOCS3 pathway: Functional Analysis of the Conserved STAT3 N-domain

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