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Cellular expression, trafficking, and function of two isoforms of human ULBP5/RAET1G

Eagle, Robert A. and Flack, Gillian and Warford, Anthony and Martínez-Borra, Jesús and Jafferji, Insiya and Traherne, James A. and Ohashi, Maki and Boyle, Louise H. and Barrow, Alexander D. and Caillat-Zucman, Sophie and Young, Neil T. and Trowsdale, John (2009) Cellular expression, trafficking, and function of two isoforms of human ULBP5/RAET1G. PLoS ONE, 4 (2). e4503. ISSN 1932-6203

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Official URL: http://dx.doi.org/10.1371/journal.pone.0004503

Abstract

Background The activating immunoreceptor NKG2D is expressed on Natural Killer (NK) cells and subsets of T cells. NKG2D contributes to anti-tumour and anti-viral immune responses in vitro and in vivo. The ligands for NKG2D in humans are diverse proteins of the MIC and ULBP/RAET families that are upregulated on the surface of virally infected cells and tumours. Two splicing variants of ULBP5/RAET1G have been cloned previously, but not extensively characterised. Methodology/Principal Findings We pursue a number of approaches to characterise the expression, trafficking, and function of the two isoforms of ULBP5/RAET1G. We show that both transcripts are frequently expressed in cell lines derived from epithelial cancers, and in primary breast cancers. The full-length transcript, RAET1G1, is predicted to encode a molecule with transmembrane and cytoplasmic domains that are unique amongst NKG2D ligands. Using specific anti-RAET1G1 antiserum to stain tissue microarrays we show that RAET1G1 expression is highly restricted in normal tissues. RAET1G1 was expressed at a low level in normal gastrointestinal epithelial cells in a similar pattern to MICA. Both RAET1G1 and MICA showed increased expression in the gut of patients with celiac disease. In contrast to healthy tissues the RAET1G1 antiserum stained a wide variety or different primary tumour sections. Both endogenously expressed and transfected RAET1G1 was mainly found inside the cell, with a minority of the protein reaching the cell surface. Conversely the truncated splicing variant of RAET1G2 was shown to encode a soluble molecule that could be secreted from cells. Secreted RAET1G2 was shown to downregulate NKG2D receptor expression on NK cells and hence may represent a novel tumour immune evasion strategy. Conclusions/Significance We demonstrate that the expression patterns of ULBP5RAET1G are very similar to the well-characterised NKG2D ligand, MICA. However the two isoforms of ULBP5/RAET1G have very different cellular localisations that are likely to reflect unique functionality.

Item Type:Article
Research Community:University of Westminster > Life Sciences, School of
ID Code:11323
Deposited On:25 Oct 2012 12:34
Last Modified:25 Oct 2012 12:34

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