Abstract
The three CARD-containing MAGUK (CARMA) proteins function as scaffolding molecules that regulate activation of the pro-inflammatory transcription factor NF-κB. Recently, mutations in CARMA2 have been linked to psoriasis susceptibility due to their acquired altered capacity to activate NF-κB. By means of two-hybrid screening with yeast, we identified RING finger protein 7 (RNF7) as an interactor of CARMA2. We present evidence that RNF7 functions as a negative regulator of the NF-κB-activating capacity of CARMA2. Mechanistically, RNF7 influences CARMA2 signaling by regulating the ubiquitination state of MALT1 and the NF-κB-regulatory molecule NEMO. Interestingly, CARMA2short (CARMA2sh) mutants associated with psoriasis susceptibility escape the negative control exerted by RNF7. In conclusion, our findings identify a new mechanism through which the ability of CARMA2 to activate NF-κB is regulated, which could have significant implications for our understanding of why mutations of this protein trigger human psoriasis.
Highlights
The CARD-containing MAGUK (CARMA) family of proteins consists of the three evolutionarily conserved proteins CARD11/CARMA1 (CARMA1), CARD14/CARMA2 (CARMA2) and CARD10/CARMA3 (CARMA3) [1,2]
While CARMA1 and CARMA3 play an essential role in NF-κB signaling induced by antigen receptors and certain G-protein-coupled receptors (GPCRs), respectively [1,2], in human keratinocytes CARMA2 plays an indispensable role in the signal transduction pathway that links pathogen-associated molecular pattern recognition to NF-κB activation [4]
When CARMA2sh, the CARMA2 isoform predominantly expressed in human keratinocytes [5,23] was used as a bait, several clones were isolated in multiple independent copies encoding for the RING finger protein 7 (RNF7), a 113-amino acid protein referred to as the sensitive to apoptosis gene (SAG) [24,25], regulator of cullins 2 (ROC2) or RING-box 2 (Rbx2)
Summary
The CARD-containing MAGUK (CARMA) family of proteins consists of the three evolutionarily conserved proteins CARD11/CARMA1 (CARMA1), CARD14/CARMA2 (CARMA2) and CARD10/CARMA3 (CARMA3) [1,2]. CARMA proteins behave as scaffolding molecules that can activate the pro-inflammatory transcription factor NF-κB [1,2]. The resulting CARMA–BCL10–MALT1 (CBM) complex mediates downstream signaling, including the recruitment and activation of the IKK complex and activation of the NK-κB pathway [1,2,3]. While CARMA1 and CARMA3 play an essential role in NF-κB signaling induced by antigen receptors and certain G-protein-coupled receptors (GPCRs), respectively [1,2], in human keratinocytes CARMA2 plays an indispensable role in the signal transduction pathway that links pathogen-associated molecular pattern recognition to NF-κB activation [4]. Many of the CARMA2 mutations associated with human skin disorders result in an increased activity of NF-κB transcription factor [2,4,5,19]. We identified RING finger-containing protein 7 (RNF7) as a novel CARMA2 interactor. We show evidence that RNF7 negatively regulates CARMA2-mediated NF-κB signaling, whereas a psoriasis-linked CARMA2 mutant escapes this negative regulation
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