The CCAAT/enhancer (C/EBP) family of basic-leucine zipper (bZIP) transcription factors is a multifaceted highly-regulated system for gene regulation

ArticleinCytokine 54(1):6-19 · April 2011with21 Reads
DOI: 10.1016/j.cyto.2010.12.019 · Source: PubMed
Abstract
The C/EBP family of proteins represents an important group of bZIP transcription factors that are key to the regulation of essential functions such as cell cycle, hematopoiesis, skeletal development, and host immune responses. They are also intimately associated with tumorigenesis and viral disease. These proteins are regulated at multiple levels, including gene induction, alternative translational initiation, post-translational modification, and protein-protein interaction. This review attempts to integrate recent reports with more than 20 years of previous effort focused on this fascinating collection of regulators.
    • "TLR signaling pathways are broadly classified into MyD88-and TRIF-dependent pathways, based on specific adaptor recruitment . These two pathways are collectively responsible for the activation of the MAPKs and IKKs, which in-turn, activate a suite of transcription factors, such as NF-kB, basic leucine zipper family members, and members of the IRF family [6,[13][14][15][16][17][18][19]. With the exception of TLR3, all TLRs recruit MyD88 as a signaling adaptor. "
    [Show abstract] [Hide abstract] ABSTRACT: Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF)-dependent signaling is required for TLR-mediated production of type-I IFN and several other proinflammatory mediators. Various pathogens target the signaling molecules and transcriptional regulators acting in the TRIF pathway, thus demonstrating the importance of this pathway in host defense. Indeed, the TRIF pathway contributes to control of both viral and bacterial pathogens through promotion of inflammatory mediators and activation of antimicrobial responses. TRIF signaling also has both protective and pathologic roles in several chronic inflammatory disease conditions, as well as an essential function in wound-repair processes. Here, we review our current understanding of the regulatory mechanisms that control TRIF-dependent TLR signaling, the role of the TRIF pathway in different infectious and noninfectious pathologic states, and the potential for manipulating TRIF-dependent TLR signaling for therapeutic benefit.
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    • "These differences in overall health between cebp-2 and zip-2 mutants may be due to CEBP-2 acting in a dimer with a different bZIP transcription factor to regulate growth and reproduction. Notably, mammalian C/EBP-gamma does not appear able to regulate transcription on its own but rather partners with several different C/EBP factors to regulate distinct outputs (Tsukada et al., 2011). Indeed, CEBP-2 has been shown in vitro to interact with several other binding partners (Reinke et al., 2013) and recently was shown to have a role in fat metabolism as well (Xu et al., 2015), which may explain its effects on body size and reproduction. "
    [Show abstract] [Hide abstract] ABSTRACT: Pathogens attack host cells by deploying toxins that perturb core host processes. Recent findings from the nematode C. elegans and other metazoans indicate that surveillance or “effector-triggered” pathways monitor functioning of these core processes and mount protective responses when they are perturbed. Despite a growing number of examples of surveillance immunity, the signaling components remain poorly defined. Here, we show that CEBP-2, the C. elegans ortholog of mammalian CCAAT-enhancer-binding protein gamma, is a key player in surveillance immunity. We show that CEBP-2 acts together with the bZIP transcription factor ZIP-2 in the protective response to translational block by P. aeruginosa Exotoxin A as well as perturbations of other processes. CEBP-2 serves to limit pathogen burden, promote survival upon P. aeruginosa infection, and also promote survival upon Exotoxin A exposure. These findings may have broad implications for the mechanisms by which animals sense pathogenic attack and mount protective responses.
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    • "Since IL-17 is a key regulator of immunity to oral candidiasis and mediates gene regulation through C/EBPβ, the impetus for this study was to understand possible connections between IL-17 signaling, C/EBPβ and antifungal immunity. The C/EBP transcription factors are central regulators of immune responses, controlling expression of a myriad of cytokines, receptors and other genes important in host defense against infection [20] . C/EBPβ [also known as liver activated protein (LAP) or nuclear factor inducing IL-6 (NF-IL6)] is an intronless gene that was among the first TFs to be characterized, yet is surprisingly poorly understood in the context of mammalian immunity. "
    [Show abstract] [Hide abstract] ABSTRACT: Humans or mice subjected to immunosuppression, such as corticosteroids or anti-cytokine biologic therapies, are susceptible to mucosal infections by the commensal fungus Candida albicans. Recently it has become evident that the Th17/IL-17 axis is essential for immunity to candidiasis, but the downstream events that control immunity to this fungus are poorly understood. The CCAAT/Enhancer Binding Protein-β (C/EBPβ) transcription factor is important for signaling by multiple inflammatory stimuli, including IL-17. C/EBPβ is regulated in a variety of ways by IL-17, and controls several downstream IL-17 target genes. However, the role of C/EBPβ in vivo is poorly understood, in part because C/EBPβ-deficient mice are challenging to breed and work with. In this study, we sought to understand the role of C/EBPβ in the context of an IL-17-dependent immune response, using C. albicans infection as a model system. Confirming prior findings, we found that C/EBPβ is required for immunity to systemic candidiasis. In contrast, C/EBPβ-/- mice were resistant to oropharyngeal candidiasis (OPC), in a manner indistinguishable from immunocompetent WT mice. However, C/EBPβ-/- mice experienced more severe OPC than WT mice in the context of cortisone-induced immunosuppression. Expression of the antimicrobial peptide β-defensin (BD)-3 correlated strongly with susceptibility in C/EBPβ-/- mice, but no other IL-17-dependent genes were associated with susceptibility. Therefore, C/EBPβ contributes to immunity to mucosal candidiasis during cortisone immunosuppression in a manner linked to β-defensin 3 expression, but is apparently dispensable for the IL-17-dependent response.
    Full-text · Article · Aug 2015
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