Indeed, CARMA1 is mainly expressed in lymphoid cells and hematopoietic tissues, where it mediates NF-κB induction following antigen receptor engagement. Despite the high degree of structural similarity, the expression pattern of each CARMA protein is restricted to distinct tissues, where they are involved in cell-specific signaling pathways that control activation of NF-κB, a pleiotropic transcription factor that controls transcription of, among others, immunomodulatory and inflammatory genes and genes that generally promote cell proliferation and survival ( 7). Structurally, CARMA proteins are characterized by a typical modular organization, with the CARD domain at the N-terminus, followed by a Coiled-Coil region and a C-terminal MAGUK domain, consisting of PDZ, SH3, and GUK modules (Figure 1A). The human CARMA proteins are encoded by three conserved genes, respectively located on chromosomes 7, 17, and 22. CARMA proteins were identified in 2001, while screening sequence databases and two-hybrid libraries for novel CARD-containing proteins, and were shown to be able to interact with the CARD domain of B-Cell Leukemia 10 (BCL10) ( 3– 6). In this review, we provide an overview on the molecular mechanisms mediating CARD14/CARMA2 signaling and its implication in our understanding of the pathogenesis of human inflammatory skin disorders.Ĭaspase recruitment domain (CARD)-containing membrane-associated guanylate kinase (MAGUK) proteins constitute a family of three scaffold proteins, highly conserved in their amino acidic sequence, named CARD11/CARMA1 (CARMA1), CARD14/CARMA2 (CARMA2), and CARD10/CARMA3 (CARMA3) ( 1, 2). The study of these molecules is important both to understand the molecular mechanisms that underlie the role of CARMA2 in keratinocytes and because they represent potential therapeutic targets for the development of therapeutic strategies aiming at the treatment of inflammatory diseases of the human skin. However, it is becoming increasingly evident that in addition to the CBM complex components, a number of accessory molecules are able to finely modulate the signals conveyed on and amplified by CARD14/CARMA2. Similarly to CARD11/CARMA1 and CARD10/CARMA3, CARD14/CARMA2 signaling occurs trough formation of a trimeric complex which includes BCL10 and MALT1 proteins. Recent evidences have shown that CARD14/CARMA2 mediates induction of inflammatory response in keratinocytes, and that mutations in CARD14/CARMA2 gene segregate with familial transmission of chronic inflammatory disorders of the human skin.
Among the CARMA proteins, CARD14/CARMA2 and its alternatively spliced isoforms are specifically expressed in epithelial cells and keratinocytes.
2Dipartimento di Scienze e Tecnologie, Università degli Studi del Sannio, Benevento, ItalyĬARMA proteins represent a family of scaffold molecules which play several crucial biological functions, including regulation of immune response and inflammation, tissue homeostasis, and modulation of G-Protein Coupled Receptor (GPCR) signaling.1Genus Biotechnology, Università degli Studi del Sannio, Benevento, Italy.Tiziana Zotti 1,2, Immacolata Polvere 1,2, Serena Voccola 1,2, Pasquale Vito 1,2 * and Romania Stilo 1,2