Telesio, Gianluca (2017) “RING finger protein-7 (RNF7) binds to and regulates the NF-κB inducing activity of the Psoriasis-linked CARMA2sh protein”. [Tesi di dottorato]

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Abstract

Psoriasis is a common immune-mediated inflammatory disease of the skin and joints. It is a chronic and essentially untreatable disease. Although genome-wide association studies have identified over 20 susceptibility loci for psoriasis, very recently only mutations in CARMA2/CARD14 have been shown to cause psoriasis dominantly and with high penetrance. The alternative splicing variant of CARMA2, CARMA2short, is the most prominent CARMA2 isoform expressed in human keratinocytes. Psoriasis-linked CARMA2 gain-of-function mutations lead to unopposed NF-κB activation and induction of inflammatory mediators from keratinocytes. We recently discovered that RNF7 (Ring Finger Protein 7) interacts with CARMA2sh. RNF7 (RING finger protein-7), also known as RBX2 (RING box protein-2), ROC2 (Regulator of cullins-2), or SAG (Sensitive to Apoptosis Gene) belongs to an evolutionarily conserved gene family with 96% sequence identity between human and mouse. RNF7 is expressed ubiquitously in human tissues with a very high expression in heart, skeletal muscle, and testis, three organs with high levels of oxygen consumption. At the subcellular level, RNF7 is expressed in both cytoplasm and nucleus. Structurally, both human and mouse RNF7 encode a protein of 113 amino acids, of which 12 are cysteine residues. At the carboxyl portion of RNF7 protein, there is a C3H2C3 motif, which chelates two zinc atoms to form the RING domain, a characteristic of a domain with E3 ubiquitin ligase activity. Here we demonstrate that RNF7 is able to dampen the ability of CARMA2sh to induce NF-κB and that CARMA2sh mutants E138A and E142G escape this form of regulation.

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