Secreted and membrane attractin result from alternative splicing of the humanATRNgene

Abstract

Attractin, initially identified as a soluble human plasma protein with dipeptidyl peptidase IV activity that is expressed and released by activated T lymphocytes, also has been identified as the product of the murine mahogany gene with connections to control of pigmentation and energy metabolism. The mahogany product, however, is a transmembrane protein, raising the possibility of a human membrane attractin in addition to the secreted form. The genomic structure of human attractin reveals that soluble attractin arises from transcription of 25 sequential exons on human chromosome 20p13, where the 3 terminal exon contains sequence from a long interspersed nuclear element-1 (LINE-1) retrotransposon element that includes a stop codon and a polyadenylation signal. The mRNA isoform for membrane attractin splices over the LINE-1 exon and includes five exons encoding transmembrane and cytoplasmic domains with organization and coding potential almost identical to that of the mouse gene. The relative abundance of soluble and transmembrane isoforms measured by reverse transcription-PCR is differentially regulated in lymphoid tissues. Because activation of peripheral blood leukocytes with phytohemagglutinin induces strong expression of cell surface attractin followed by release of soluble attractin, these results suggest that a genomic event unique to mammals, LINE-1 insertion, has provided an evolutionary mechanism for regulating cell interactions during an inflammatory reaction.T he regulation of the basic inflammatory response, involving recognition, recruitment of helper and effector cells, and their subsequent down-regulation, requires a complex interplay of cells, their receptors, and secreted cytokines and chemokines (1). We recently have identified the soluble human plasma protein attractin as a molecule that can facilitate initial immune cell clustering (2) and, through a putative dipeptidyl peptidase IV (DPPIV) activity similar to that of CD26 (3), has the potential to regulate chemotactic activity of chemokines (4). These activities would be required at differing stages of the inflammatory process and suggest that the functional activities of attractin may operate independent of its actual plasma levels, much as is seen for the components of complement that circulate normally at constant levels but are only active in the context of ''fixed'' antibody during the effector phase of a humoral response. Initial evidence for controlled expression of attractin was provided by the finding that not only was attractin a soluble protein but that its expression was induced early in T cell activation with a subsequent loss of membrane expression followed by release of soluble attractin (3).Two recent reports describe the identification of a membrane form of attractin as the product of the murine mahogany gene, establishing connections to control of pigmentation and energy metabolism (5, 6). A predicted Caenorhabditis elegans protein, F33C8.1, is also homologous to attractin and is a transmembrane rather than a soluble protein...

Retroelements and the human genome: New perspectives on an old relation

“…Both forms, the transmembrane and the soluble protein, are involved in cell interactions during inflammatory processes. Thus, a retroelement insertion has provided an evolutionary mechanism for regulating an inflammatory response (75). Apart from polyadenylation sites, retroelements may also provide splice sites and other transcriptional processing signals that are often used in a cell-type-specific manner.…”

The Myelin Vacuolation (mv) Rat with a Null Mutation in the Attractin Gene

“…T he human ATRN is a glycoprotein consisting of two isoforms, membrane-type (200 kDa) and secreted-type (175 kDa) as a result of alternative splicing (Duke-Cohan et al, 1998;Gunn et al, 1999;Nagle et al, 1999;Tang et al, 2000). The identification and function of the ATRN have been investigated from immunologic aspects in a secreted form.…”

New Insights into G-Protein-Coupled Receptor Signaling from the Melanocortin Receptor System

“…The product of the murine mahogany locus was cloned and found to be expressed in many cells and tissues, including melanocytes and the hypothalamus (Gunn et al, 1999). It is orthologous to a transmembrane domain-coding splice variant of the human attractin molecule (Tang et al, 2000). The mechanism of action of this membrane-bound protein is also not fully understood; however, He et al (2001) provided biochemical evidence of a mechanism in which the mahogany product, attractin, functions as a low-affinity receptor for agouti, but not for AGRP, that increases its local cell-surface concentration, enabling agouti to antagonize the action of ␣-MSH on MC1R and, when ectopically expressed, on MC4R (Fig.…”