NFATc2 recruits cJun homodimers to an NFAT site to synergistically activate interleukin-2 transcription

Abstract

Transcription of interleukin-2 (IL-2), a pivotal cytokine in the mammalian immune response, is induced by NFAT and AP-1 transcriptional activators in stimulated T cells. NFATc2 and cJun drive high levels of synergistic human IL-2 transcription, which requires a unique interaction between the C-terminal activation domain of NFATc2 and cJun homodimers. Here we studied the mechanism by which this interaction contributes to synergistic activation of IL-2 transcription. We found that NFATc2 can recruit cJun homodimers to the −45 NFAT element, which lacks a neighboring AP-1 site. The bZip domain of cJun is sufficient to interact with the C-terminal activation domain of NFATc2 in the absence of DNA and this interaction is inhibited by AP-1 DNA. When the −45 NFAT site was replaced by either a NFAT/AP-1 composite site or a single AP-1 site the specificity for cJun homodimers in synergistically activating IL-2 transcription was lost, and cJun/cFos heterodimers strongly activated transcription. These studies support a model in which IL-2 transcriptional synergy is mediated by the unique recruitment of a cJun homodimer to the −45 NFAT site by NFATc2, where it acts as a co-activator for IL-2 transcription.

Aptamers: Uptake mechanisms and intracellular applications

“…In competition assay, the anti-cJun aptamer blocked the homodimerization of cJun from binding AP-1 DNA. The cJun homodimers are not only capable of binding cis-elements on DNA to activate transcription but can also function as transcriptional co-activators by binding directly to other transcription factors NFATc2 for synergistic activation of interleukin 2 (IL-2) [111]. Therefore to determine the biological function of anti-cJun homodimer DNA aptamers, the transcriptional inhibition of IL-2 was assayed.…”

Co-Stimulation–Induced AP-1 Activity is Required for Chromatin Opening During T Cell Activation

“…The Il2 promoter has several AP-1 and NFAT binding sites that are conserved between human and mouse (Rooney et al, 1995;Macian et al, 2001). The binding sites are adjacent, and AP-1 and NFAT form a heteromer (Jain et al, 1994;Chen et al, 1998) and synergize to induce Il2 expression (Walters et al, 2013;Nguyen et al, 2010). Mutation of these binding sites prevents Il2 expression (Walters et al, 2013).…”

Identification and Functional Characterization of Novel Genetic Variations in Porcine TLR5 Promoter

“…The identification of CCAAT-Boxes located upstream of SP1 and TFIID transcription factor targets (from -540 to -604), the high occurrence of ZF02 binding sites, and the identification of a CpG island, including GC-rich sites, suggests that all these elements form a transcriptional regulatory complex (Yang et al, 2007). In addition, putative transcription factor binding sites commonly found in the promoter regions of genes involved in the immune responses were identified, strongly suggesting the high regulatory ability of this region on the porcine TLR5 transcriptional activity (Kielland and Carlsen, 2010;Burke et al, 2014;Walters et al, 2013).…”