EXPRESSION ANALYSIS AND CHARACTERIZATION OF ALTERNATIVELY SPLICED TRANSCRIPTS OF HUMAN IL-7Rα CHAIN ENCODING TWO TRUNCATED RECEPTOR PROTEINS IN RELAPSED CHILDHOOD ALL

Korte, Alexander; Köchling, Joachim; Badiali, Lucia; Eckert, Cornelia; Andreae, Jörn; Geilen, Wilhelm; Kebelmann-Betzing, Christian; Taube, Tillmann; Wu, Shuling; Henze, Günter; Seeger, K.

doi:10.1006/cyto.2000.0777

Cited by 27 publications

(15 citation statements)

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“…Underscoring its importance in T cell biology, aberrant expression of IL7R has been implicated in several human diseases such as severe combined immunodeficiency (SCID) (Puel et al 1998;Kalman et al 2004) and acute lymphoblastic leukemia (Korte et al 2000;Zhang et al 2012), while genetic variation in IL7R can predispose to such diseases as sarcoidosis (Heron et al 2009), primary biliary cirrhosis (Mells et al 2011), ulcerative colitis (Yamazaki et al 2003;Anderson et al 2011), MS (Gregory et al 2007), and others, suggesting a larger role for this gene in the pathogenesis of autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

“…Several splicing isoforms have been reported for IL7R at the RNA level (Goodwin et al 1990;Pleiman et al 1991;Korte et al 2000;Gregory et al 2007;Rose et al 2009), but efforts to characterize these splicing events in detail have not been made. Moreover, to the best of our knowledge, other mechanisms of post-transcriptional regulation of IL7R expression, such as regulation by alternative polyadenylation, have not been explored.…”

Section: Cpsf1 Regulates Alternative Splicing Of Il7rmentioning

confidence: 99%

“…Given that exon 6 encodes the transmembrane domain of the receptor (Pleiman et al 1991), its alternative splicing leads to a membrane-bound isoform (rIL7R) when exon 6 is included, and a soluble isoform (sIL7R) when exon 6 is skipped. sIL7R lacks both the transmembrane and cytoplasmic domains of the receptor (Goodwin et al 1990; Korte et al 2000; for review, see Evsyukova et al 2010). Importantly, both isoforms are able to bind IL7 with high affinity (Goodwin et al 1990;Rose et al 2009).…”

Section: Introductionmentioning

confidence: 99%

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Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6

Evsyukova

Bradrick²,

Gregory

et al. 2012

RNA

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Interleukin 7 receptor, IL7R, is expressed exclusively on cells of the lymphoid lineage, and its expression is crucial for the development and maintenance of T cells. Alternative splicing of IL7R exon 6 results in membrane-bound (exon 6 included) and soluble (exon 6 skipped) IL7R isoforms. Interestingly, the inclusion of exon 6 is affected by a single-nucleotide polymorphism associated with the risk of developing multiple sclerosis. Given the potential association of exon 6 inclusion with multiple sclerosis, we investigated the cis-acting elements and trans-acting factors that regulate exon 6 splicing. We identified multiple exonic and intronic cis-acting elements that impact inclusion of exon 6. Moreover, we utilized RNA affinity chromatography followed by mass spectrometry to identify trans-acting protein factors that bind exon 6 and regulate its splicing. These experiments identified cleavage and polyadenylation specificity factor 1 (CPSF1) among protein-binding candidates. A consensus polyadenylation signal AAUAAA is present in intron 6 of IL7R directly downstream from the 59 splice site. Mutations to this site and CPSF1 knockdown both resulted in an increase in exon 6 inclusion. We found no evidence that this site is used to produce cleaved and polyadenylated mRNAs, suggesting that CPSF1 interaction with intronic IL7R pre-mRNA interferes with spliceosome binding to the exon 6 59 splice site. Our results suggest that competing mRNA splicing and polyadenylation regulate exon 6 inclusion and consequently determine the ratios of soluble to membrane-bound IL7R. This may be relevant for both T cell ontogeny and function and development of multiple sclerosis.

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Section: Discussionmentioning

confidence: 99%

Section: Cpsf1 Regulates Alternative Splicing Of Il7rmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6

Evsyukova

Bradrick²,

Gregory

et al. 2012

RNA

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“…CD86 [28], Fas [30], IL7Ra [29] and LILRB4 [3]) or by proteolytic cleavage from the cell surface (e.g. NKG2D ligands [31][32][33]) to divert immune responses.…”

Section: Discussionmentioning

confidence: 99%

“…The production of soluble forms of cell surface immunoregulatory molecules may influence immune responses and can be exploited by tumours as a means of immune evasion [3,[28][29][30][31][32][33]. These soluble molecules may arise by proteolytic cleavage from the cell surface by matrix metalloproteinases [31][32][33][34].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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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...

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Interleukin (IL)-7 Signaling in the Tumor Microenvironment

Bednarz−Misa

Bromke

Krzystek−Korpacka

2021

Advances in Experimental Medicine and Biology

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EXPRESSION ANALYSIS AND CHARACTERIZATION OF ALTERNATIVELY SPLICED TRANSCRIPTS OF HUMAN IL-7Rα CHAIN ENCODING TWO TRUNCATED RECEPTOR PROTEINS IN RELAPSED CHILDHOOD ALL

Cited by 27 publications

References 47 publications

Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6

Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6

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

Interleukin (IL)-7 Signaling in the Tumor Microenvironment

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