Abstract
The caspase recruitment domain (CARD)-containing proteins CARMA1-3 share high degree of sequence, structure and functional homology. Whereas CARMA1 and CARMA3 have been identified as crucial components of signal transduction pathways that lead to activation of NF-κB transcription factor, little is known about the function of CARMA2. Here we report the identification of two splice variants of CARMA2. One transcript, named CARMA2short (CARMA2sh), is predicted to encode for a CARMA2 polypeptide containing the CARD, coiled coil, and a PDZ domains, but lacking the SH3 and the GuK domains. The second variant, CARMA2cardless (CARMA2cl), encodes for a polypeptide lacking the CARD domain and containing only a portion of the coiled coil domain and a linker region. Expression analysis confirmed the presence of the CARMA2 alternatively spliced transcripts in both human cell lines and tissues. Fluorescence microscopy data show that both splice variants localize in the cytosol. Biochemical experiments indicate that CARMA2sh interacts with TRAF2 and activates NF-κB in a TRAF2-dependent manner. Finally, CARMA2sh variant protects cells from apoptosis induced by different stimuli. Taken together, these results demonstrate that multiple transcripts encoding several CARMA2 isoforms exist in vivo and regulate NF-κB activation and apoptosis. J. Cell. Physiol. 226: 3121–3131, 2011. © 2011 Wiley Periodicals, Inc.
Highlights
To examine the occurrence of splice variants derived from the human CARMA2 gene, we performed an extensive reverse transcriptionpolymerase chain reaction (RT-PCR) analysis of mRNAs isolated from human cell lines using CARMA2/CARD14 exon-specific primers
Since TRAF2 regulates apoptotic signal transduction pathways starting from membrane receptors and the endoplasmic reticulum (ER) membrane (Rothe et al, 1994; Yoneda et al, 2001; Mauro et al, 2006), we investigated the involvement of CARMA2sh in cell death induced by different stimuli
We describe the identification and the functional characterization of two novel isoforms of CARMA2, namely CARMA2sh and CARMA2cl
Summary
The caspase recruitment domain (CARD)-containing proteins CARMA1 (CARD11/Bimp2) (Bertin et al, 2001; Gaide et al, 2001; Wang et al, 2001), CARMA2 (CARD14/Bimp3) (Bertin et al, 2001), and CARMA3 (CARD10/Bimp1) (Wang et al, 2001; McAllister-Lucas et al, 2001) share a high degree of sequence, structure, and functional homology. Genetic and biochemical studies have identified CARMA1 as crucial component of a complex of proteins that links antigen receptors on B and T lymphocytes to activation of NF-kB (Wang et al, 2002; Gaide et al, 2002; Pomerantz et al, 2002; Hara et al, 2003; Egawa et al, 2003; Newton and Dixit, 2003; Jun et al, 2003) This complex, which includes CARMA1, BCL10, MALT1, and TRAF6, has been shown to activate the IKK complex through an ubiquitylationdependent pathway (Schulze-Luehrmann and Ghosh, 2006). We describe the identification of two splice variants of CARMA2 and show data indicating an involvement of these proteins in regulation of NF-kB activation and endoplasmic reticulum (ER)-stress induced cell death
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