Abstract
c-Jun is a major component of the dimeric transcription factor activator protein-1 (AP-1), a paradigm for transcriptional response to extracellular signaling, whose components are basic-Leucine Zipper (bZIP) transcription factors of the Jun, Fos, activating transcription factor (ATF), ATF-like (BATF) and Jun dimerization protein 2 (JDP2) gene families. Extracellular signals regulate c-Jun/AP-1 activity at multiple levels, including transcriptional and posttranscriptional regulation of c-Jun expression and transactivity, in turn, establishing the magnitude and the duration of c-Jun/AP-1 activation. Another important level of c-Jun/AP-1 regulation is due to the capability of Jun family members to bind DNA as a heterodimer with every other member of the AP-1 family, and to interact with other classes of transcription factors, thereby acquiring the potential to integrate diverse extrinsic and intrinsic signals into combinatorial regulation of gene expression. Here, we review how these features of c-Jun/AP-1 regulation underlie the multifaceted output of c-Jun biological activity, eliciting quite distinct cellular responses, such as neoplastic transformation, differentiation and apoptosis, in different cell types. In particular, we focus on the current understanding of the role of c-Jun/AP-1 in the response of CD8 T cells to acute infection and cancer. We highlight the transcriptional and epigenetic regulatory mechanisms through which c-Jun/AP-1 participates in the productive immune response of CD8 T cells, and how its downregulation may contribute to the dysfunctional state of tumor infiltrating CD8 T cells. Additionally, we discuss recent insights pointing at c-Jun as a suitable target for immunotherapy-based combination approaches to reinvigorate anti-tumor immune functions.
Highlights
Active activator protein-1 (AP-1) is a dimeric complex whose components are basic-Leucine Zipper transcription factors (TFs) of the Jun, Fos, activating transcription factor (ATF), ATF-like (BATF) and Jun dimerization protein 2 (JDP2) gene families, binding DNA as an obligate dimer through their bZIP domain, with DNA-binding preferences being partner-specific [1]
This study showed that a nuclear factor of activated T cells (NFAT)-1 variant unable to interact with c-Jun/AP-1 induces a transcriptional program establishing T cell exhaustion [21]
These findings indicate that a NFAT/AP-1/interferon responsive factor 4 (IRF4) composite site (NAICE) directs the assembly of NFAT/BATF/IRF4 complexes at genes regulating CD8+ T cell exhaustion; whereas in effector CD8 T cells, the AP-1-IRF composite sites (AICE) composite site directs JUN/BATF/IRF4 complexes at genes regulating effector differentiation (Figure 3A,B) [6,138]
Summary
Active AP-1 is a dimeric complex whose components are basic-Leucine Zipper (bZIP) transcription factors (TFs) of the Jun, Fos, activating transcription factor (ATF), ATF-like (BATF) and Jun dimerization protein 2 (JDP2) gene families, binding DNA as an obligate dimer through their bZIP domain, with DNA-binding preferences being partner-specific [1]. Further studies have shown that partnerless NFAT activates secondary TFs, such as the HMG-box transcription factor TOX and nuclear receptor 4a (NR4A), in turn promoting chromatin accessibility at genes driving CD8 T cell exhaustion in chronic infection and cancer [25,26,27,28,29] These same TFs were shown to drive exhaustion in CD8 T cells engineered to express chimeric antigen receptors (CAR T cells) for the targeting of solid tumors [29,30,31]. The elucidation of the core transcriptional pathway initiating T cell exhaustion in different settings has opened the road to more effective immunotherapeutic strategies, aiming to reinvigorate T cell responses In this regard, recent studies have shown that CAR T cells deficient in either TOX or NR4A exhibit a gene expression profile characteristic of CD8 effector T cells, with open chromatin regions enriched for both NF-κB and c-Jun/AP-1 binding motifs [29,31]. We discuss the epigenetic and transcriptional mechanisms through which c-Jun/Ap1 contributes to the productive immune response of CD8 T cells, and how its deregulation in tumor reactive CD8 T cells may facilitate T cell dysfunction
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