Alternative mRNA splicing creates transcripts encoding soluble proteins from most LILR genes

Abstract

Leucocyte Ig-like receptors (LILR) are a family of innate immune receptors expressed on myeloid and lymphoid cells that influence adaptive immune responses. We identified a common mechanism of alternative mRNA splicing, which generates transcripts that encode soluble protein isoforms of the majority of human LILR. These alternative splice variants lack transmembrane and cytoplasmic encoding regions, due to the transcription of a cryptic stop codon present in an intron 5 0 of the transmembrane encoding exon. The alternative LILR transcripts were detected in cell types that express their membrane-associated isoforms. Expression of the alternative LILRB1 transcript in transfected cells resulted in the release of a soluble $65 Kd LILRB1 protein into culture supernatants. Soluble LILRB1 protein was also detected in the culture supernatants of monocyte-derived DC. In vitro assays suggested that soluble LILRB1 could block the interaction between membrane-associated LILRB1 and HLAclass I. Soluble LILRB1 may act as a dominant negative regulator of HLA-class I-mediated LILRB1 inhibition. Soluble isoforms of the other LILR may function in a comparable way.Key words: Alternative splicing . Leucocyte Ig-like receptor . Ig-like transcript . Secreted . Soluble Supporting Information available online IntroductionThe human leukocyte Ig-like receptors (LILR) (also known as LIR, Ig-like transcripts (ILT) and CD85) are innate immune receptors related to the killer Ig-like receptors (KIR). The expression and signalling activity of LILR on professional APC can have a potent modulating effect on T-cell responses [1][2][3][4]. The LILR gene family consists of 11 genes and two pseudogenes [5][6][7] and is located within the leukocyte receptor complex on chromosome 19q13.4, centromeric of the KIR gene cluster. LILR encode type I transmembrane (TM) Ig super family proteins that are expressed on both myeloid and lymphocyte cells [6]. The extracellular region of a mature LILR protein consists of either two or four Ig domains coupled to a stalk region, which in turn is linked to the TM portion of the molecule. LILR can be divided into three groups based on their signalling capability: those that possess a long cytoplasmic tail, containing ITIM, generate inhibitory signalling [8][9][10][11]; LILR possessing an arginine within their TM region and a short cytoplasmic tail signal through association with the adaptor molecule FcRg, which encodes an ITAM [12,13]; finally, the soluble protein LILRA3 has no known signalling ability [9,14,15]. Several LILR act as receptors for HLA-class I molecules. The best characterised of these is the inhibitory receptor LILRB1 (ILT2/LIR1/ CD85j). In contrast to KIR, which recognise dimorphic epitopes Eur. J. Immunol. 2009. 39: 3195-3206 DOI 10.1002 [9,14,15]; the product of the LILRA3 gene lacks a TM and cytoplasmic encoding domain, although the LILRA3 genomic sequence contains pseudoexons highly homologous to exons encoding these domains in LILRA1 [37]. The exon encoding the extracellular stalk region of LILRA...

Voltage-Gated Na+Channel β1B: A Secreted Cell Adhesion Molecule Involved in Human Epilepsy

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Identification of protein features encoded by alternative exons using Exon Ontology

“…2C, "Intramembrane Polypeptide Region" [IPR]; Supplemental Table S3). This observation suggests that alternative splicing may impact the ability of proteins to be incorporated into cellular membranes as was reported in a few cases (Stamm et al 2005;Jones et al 2009;Tejedor et al 2015). Even though we do not know yet the biological meaning of the enrichment for some protein features in different exon categories, we believe these data are important to underscore the importance of using an appropriate set of control exons.…”

Leukocyte immunoglobulin-like receptor B1 is critical for antibody-dependent dengue

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