Polymorphisms of NKG2D ligands: diverse RAET1/ULBP genes in Northeastern Thais

Abstract

Unique long 16 (UL-16)-binding proteins (ULBP) or retinoic acid early transcripts-1 (RAET1) are ligands to the activating receptor, NKG2D. The human RAET1/ULBP gene family is identified as ten members (RAET1E to N) with six loci encoding for potentially functional proteins. These are ULBP1 or RAET1I, ULBP2 or RAET1H, ULBP3 or RAET1N, and RAET1L, which are glycosylinositol phospholipid (GPI)-linked glycoproteins and ULBP4 or RAET1E and ULBP5 or RAET1G, which are transmembrane glycoproteins. The RAET1 products contain the alpha1 and alpha2 domains but lack the alpha3 domain and do not associate with beta2-microglobulin. RAET1/ULBPs have tissue-specific expressions, and some of them are also polymorphic. In the present study, polymorphic exons 2 and 3 of the RAET1E, G, H, I, L, and N were analyzed using sequence-based typing. One hundred and seventy-six unrelated healthy Northeastern Thais were included in this study. For RAET1E, RAET1G, RAET1H, and RAET1L, there were seven, two, five, and four single nucleotide polymorphisms (SNPs), respectively. Six of these are new SNPs, which are rare in this population. Of these, six new SNPs, two of two in RAET1E, two of three in RAET1H, and none of one in RAET1L are nonsynonymous substitutions. Interestingly, although the RAET1N is polymorphic in Caucasians, RAET1N and RAET1I had no variation in Thais indicating diverse RAET1 genes in different ethnic groups. These data provide the important basis for future analysis on the role of RAET1 genes in immune responses especially in cancer and infectious diseases.

NK cell activating receptor ligand expression in lymphangioleiomyomatosis is associated with lung function decline

“…Specific ULBP NKG2DLs may also contribute to disease pathogenesis -for example, in alopecia areata (56). However, haplotype specific contributions of ULBPs to disease pathophysiology have yet to be elucidated (57). Heterogeneity in TSC1/2 mutations may also contribute to alterations in downstream signaling that result in differential upregulation of NKG2DL expression.…”

NKG2D‐ligands: Putting everything under the same umbrella can be misleading

“…The RAET1/ULBP genes also show variation, mainly through single nucleotide polymorphisms in both the promoter region and coding sequence . Even though ULBP polymorphism is generally less than that observed for MICA/B molecules it can still be functionally significant.…”

Manipulation of NKG2D ligands by cytomegaloviruses: impact on innate and adaptive immune response

“…There is also some degree of polymorphism in RAET-1 genes and mouse H60 and RAE-1 genes (Eagle et al, 2006; Romphruk et al, 2009). The reason for such a high degree of polymorphism is unknown at the present but it may have evolved to counter the selective pressure formed by pathogens and their evasion strategies, in order to maintain a proper recognition of infected cells by NK cells.…”