Activation-induced Tumor Necrosis Factor Receptor-associated Factor 3 (Traf3) Alternative Splicing Controls the Noncanonical Nuclear Factor κB Pathway and Chemokine Expression in Human T Cells

Michel, Monika; Wilhelmi, Ilka; Schultz, Astrid-Solveig; Preußner, Marco

doi:10.1074/jbc.m113.526269

Cited by 23 publications

(28 citation statements)

References 40 publications

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“…Traf3DE8 disrupts the interaction of TRAF2 and NIK, preventing degradation of the latter. 85 This study confirms the diverse roles of TRAF3 in NFkB2 activation and the need to further explore all roles of TRAF3 in T cell biology.…”

Section: Nf-kb2 Signaling In T Cellssupporting

confidence: 60%

Roles of TRAF3 in T cells: many surprises

Wallis

Bishop

2015

Cell Cycle

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Tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3) is broadly involved in different receptor-mediated signaling pathways. Considerable progress was made recently in understanding the role of TRAF3 in T cell biology. Here we review these new findings about how TRAF3 participates in T cell development and function. The different roles of TRAF3 in distinct immune cells are also compared. That TRAF3 is required for T cell effector functions, and invariant Natural Killer T cell function and development, was unexpected. Another surprising finding is that TRAF3 normally restrains regulatory T cell development. It is now clear that TRAF3 regulates signaling to T cells not only through costimulatory members of the TNFR superfamily, but also through the T cell receptor complex, and cytokine receptors. The diverse roles it plays support the multifaceted nature of this molecule. How TRAF3 mediates integration of different signaling cascades is an important topic for future study.

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Section: Nf-kb2 Signaling In T Cellssupporting

confidence: 60%

Roles of TRAF3 in T cells: many surprises

Wallis

Bishop

2015

Cell Cycle

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“…Formation of this complex in unstimulated T cells leads to constant NIK degradation and low basal NIK expression. NIK can therefore only accumulate in activated, TRAF3ΔE8-expressing T cells, where it triggers the activation of ncNF-B signaling (31). In the present work, we have identified the mechanistic basis for activation-dependent and cell-type-specific TRAF3 exon 8 skipping.…”

mentioning

confidence: 73%

“…However, these data did not address the question whether CELF2 expression alone is sufficient to regulate alternative splicing or if this requires additional signals, e.g., posttranslational modifications in activated T cells. To this end, we turned to two human B cell lines, Raji and Ramos, that we have previously shown to be unresponsive to PMA treatment with respect to TRAF3 alternative splicing (31) (Fig. 4A).…”

Section: Resultsmentioning

confidence: 99%

“…RNA extraction, reverse transcription-PCR (RT-PCR), phosphorimager quantification, and reverse transcription-quantitative PCR (RT-qPCR) were all performed as previously described (31,47). The percent PMA-induced exon skipping was defined as % inclusion without PMA treatment Ϫ % inclusion with PMA stimulation.…”

Section: Methodsmentioning

confidence: 99%

“…We have recently shown that exclusion of TRAF3 exon 8 is increased upon T cell activation and induces ncNF-B signaling to control chemokine expression (31). This induction is based on differential interaction of the two TRAF3 isoforms with the kinase NIK, which, upon activation-induced exclusion of TRAF3 exon 8, is released from a ubiquitin-ligase complex.…”

mentioning

confidence: 99%

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Activation-Dependent TRAF3 Exon 8 Alternative Splicing Is Controlled by CELF2 and hnRNP C Binding to an Upstream Intronic Element

Schultz

Preußner

Bunse

et al. 2017

Molecular and Cellular Biology

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Cell-type-specific and inducible alternative splicing has a fundamental impact on regulating gene expression and cellular function in a variety of settings, including activation and differentiation. We have recently shown that activationinduced skipping of TRAF3 exon 8 activates noncanonical NF-B signaling upon T cell stimulation, but the regulatory basis for this splicing event remains unknown. Here we identify cis-and trans-regulatory elements rendering this splicing switch activation dependent and cell type specific. The cis-acting element is located 340 to 440 nucleotides upstream of the regulated exon and acts in a distance-dependent manner, since altering the location reduces its activity. A small interfering RNA screen, followed by cross-link immunoprecipitation and mutational analyses, identified CELF2 and hnRNP C as trans-acting factors that directly bind the regulatory sequence and together mediate increased exon skipping in activated T cells. CELF2 expression levels correlate with TRAF3 exon skipping in several model systems, suggesting that CELF2 is the decisive factor, with hnRNP C being necessary but not sufficient. These data suggest an interplay between CELF2 and hnRNP C as the mechanistic basis for activation-dependent alternative splicing of TRAF3 exon 8 and additional exons and uncover an intronic splicing silencer whose full activity depends on the precise location more than 300 nucleotides upstream of the regulated exon.KEYWORDS RNA binding proteins, RNA splicing S plicing-sensitive microarrays and transcriptome sequencing (RNA-Seq) technologies have led to the accumulation of enormous amounts of gene expression data from different cell types and tissues under various conditions. Such analyses have led to the conclusion that the majority of human genes are alternatively spliced and have shown strong differences in global splicing patterns under different conditions (1-3). Although these differences suggest a substantial contribution of alternative splicing to the regulation of gene expression, studies connecting alternative splicing and functionality are rare. Consequently, a functional impact of individual alternative splicing events on cellular functionality was demonstrated for only a few examples (4-7), and the function of most alternative splicing events remains unknown. However, a recent large-scale approach demonstrated that splice-isoforms of the same gene often have distinct protein-protein interaction profiles, further supporting the notion of distinct functionality (8).Another largely open question concerns splicing regulation: how are cell-typespecific splicing patterns established and maintained? Despite the identification of

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