Naturally occurring C-terminal splice variants of nuclear receptors

Abstract

Alternative mRNA splicing in the region encoding the C-terminus of nuclear receptors results in receptor variants lacking the entire ligand-binding domain (LBD), or a part of it, and instead contain a sequence of splice variant-specific C-terminal amino acids. A total of thirteen such splice variants have been shown to occur in vertebrates, and at least nine occur in humans. None of these receptor variants appear to be able to bind endogenous ligands and to induce transcription on promoters containing the response element for the respective canonical receptor variant. Interestingly, ten of these C-terminal splice variants have been shown to display dominant-negative activity on the transactivational properties of their canonical equivalent. Research on most of these splice variants has been limited, and the dominant-negative effect of these receptor variants has only been demonstrated in reporter assays in vitro, using transiently transfected receptors and reporter constructs. Therefore, the in vivo function and relevance of most C-terminal splice variants remains unclear. By reviewing the literature on the human glucocorticoid receptor β-isoform (hGRβ), we show that the dominant-negative effect of hGRβ is well established using more physiologically relevant readouts. The hGR β-isoform may alter gene transcription independent from the canonical receptor and increased hGRβ levels correlate with glucocorticoid resistance and the occurrence of several immune-related diseases. Thus, available data suggests that C-terminal splice variants of nuclear receptors act as dominant-negative inhibitors of receptor-mediated signaling in vivo, and that aberrant expression of these isoforms may be involved in the pathogenesis of a variety of diseases.

A naturally occurring truncated Cav1.2 α1-subunit inhibits Ca2+ current in A7r5 cells

“…The suggestion that a nonfunctional gene product produced naturally by alternative splicing may play a role in the regulation of full-length protein activity is not new (15). There are numerous examples in the literature where such a role has been demonstrated for truncated isoforms of G protein-coupled receptors (37), nuclear receptors (36), and other ion channels (26), as well as other proteins (16). In many of these cases, critical domains are lost as a result of the alternative splicing, rendering such truncated isoforms nonfunctional, leading to their retention within the cell, where they form heterodimers with full-length isoforms.…”

“…In many of these cases, critical domains are lost as a result of the alternative splicing, rendering such truncated isoforms nonfunctional, leading to their retention within the cell, where they form heterodimers with full-length isoforms. This reduces trafficking of fulllength functional proteins to the plasma membrane (or to other cell compartments), thereby decreasing the protein's functional activity (26,36). In some cases, the abundance of the spliced isoform is directly regulated, contributing to the regulation of full-length isoform activity (12,16).…”

Xenobiotic-sensing nuclear receptors involved in drug metabolism: a structural perspective

“…There are 26 splice variants (Lamba et al, 2004) for full-length CAR, with CAR LBD variants involving the entire deletion of exon 5 and/or 7 (Lamba et al, 2004; van der Vaart and Schaaf, 2009), as well as deletions of exon 4 (which constitutes a portion of the N-terminal LBD), partial deletions of exon 9 (C-terminal end), and insertions throughout the LBD. The major splice variants of CAR involve the deletion of exon 7 (Figure 5B), which includes variants 3, 5, 8–11, and 16–21, and involve the elimination of major helices that line the ligand-binding pocket.…”

Investigation of the dominant positive effect of porcine farnesoid X receptor (FXR) splice variant 1

“…This has been seen with a variant of the glucocorticoid receptor, termed glucocorticoid receptor β (GRβ), which differs from the wildtype receptor (GRα) by having the final 50 amino acids of the protein replaced with 15 unique residues (Bamberger et al, 1995). Increased formation of GRβ has been shown to reduce the response to glucocorticoid treatment in patients suffering from a variety of immune-related diseases, including systemic lupus erythematosus (van der Vaart and Schaaf, 2009;Piotrowski et al, 2007). This dominant negative effect has also been shown with human estrogen receptor, both human and mouse CAR, and the rat vitamin D receptor variants (van der Vaart and Schaaf, 2009).…”

“…Increased formation of GRβ has been shown to reduce the response to glucocorticoid treatment in patients suffering from a variety of immune-related diseases, including systemic lupus erythematosus (van der Vaart and Schaaf, 2009;Piotrowski et al, 2007). This dominant negative effect has also been shown with human estrogen receptor, both human and mouse CAR, and the rat vitamin D receptor variants (van der Vaart and Schaaf, 2009). …”