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

•Only a single NFAT element at −45 is essential for transcriptional synergy by NFATc2 and cJun.•IL-2 transcriptional synergy is sensitive to the helical phasing between the −45 NFAT element and the transcriptional start site.•NFATc2 can recruit cJun to the −45 NFAT site in the absence of an AP-1 site.•The bZip domain of cJun is sufficient to interact with the C-terminal activation domain of NFATc2 and this interaction is blocked by AP-1 DNA.•An AP-1 DNA element can replace the −45 NFAT site to mediate transcriptional synergy.

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 an 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.