Ashiru, OmodeleLópez-Cobo, SheilaFernández Messina, Lola MaríaLola Fernández-MessinaPontes-Quero, SamuelPandolfi, RacheleReyburn, Hugh Valés-Gómez, Mar2024-01-312024-01-312013Ashiru, Omodele, et al. «A GPI Anchor Explains the Unique Biological Features of the Common NKG2D-Ligand Allele MICA*008». Biochemical Journal, vol. 454, n.o 2, septiembre de 2013, pp. 295-302. https://doi.org/10.1042/BJ20130194.0264-602110.1042/bj20130194https://hdl.handle.net/20.500.14352/97172FUNDING This work was supported by the Medical Research Council [New Investigator grant number G0601165 (to M.V.-G.)], the Royal Society [grant number IJP2007/R3] and Fondo de Investigación Sanitaria [grant numbers PS09/00181, PI08/1701 and PI11/00298]. O.A. was partially supported by The Newton Trust and the Leukaemia Research Fund [grant number 05060 (to H.T.R. and M.V.-G.)]; S.L.-C. was partially supported by CSIC (Consejo Superior de Investigaciones Científicas) [grant number 201020E086 (to M.V.-G.)]; L.F.-M. was partially supported by CSIC [grant 201020I044 (to M.V.-G.)] and the Comunidad de Madrid [grant number S2010/BMD-2326 IMMUNOTHERCAN (to M.V.-G.)]; R.P. was an exchange student of the Leonardo da Vinci program; and S.P.-Q. was a recipient of a CSIC fellowship of Introduction to Research.The human MICA (MHC I-related chain A) gene, encoding a ligand for the NKG2D (NKG2-D type II integral membrane protein) receptor, is highly polymorphic. A group of MICA alleles, named MICA 5.1 (prototype, MICA*008), produce a truncated protein due to a nucleotide insertion in the transmembrane domain. These alleles are very frequent in all of the human populations studied and they have different biological properties, compared with full-length alleles, e.g. recruitment into exosomes, which makes them very potent for down-modulating the NKG2D receptor in effector immune cells. Moreover, MICA*008 is not affected by viral immune evasion mechanisms that target other MICA alleles. In the present study, we demonstrate that MICA*008 acquires a GPI (glycosylphosphatidylinositol) anchor and that this modification is responsible for many of the distinct biological features of the truncated MICA alleles, including recruitment of the protein to exosomes. MICA*008 processing is also unusual as it is observed in the endoplasmic reticulum as a Triton™ X-114 soluble protein, partially undergoing GPI modification while the rest is exocytosed, suggesting a new model for MICA*008 release. This is the first report of a GPI-anchored MICA allele. The finding that this modification occurs in both families of human NKG2D ligands, as well as in the murine system, suggests positive pressure to maintain this biochemical feature.engjournal article1470-8728https://doi.org/10.1042/BJ20130194restricted access577.21ExosomeGlycosylphosphatidylinositol (GPI)-anchored proteinhuman NKG2D-ligandMICA polymorphismNKG2-D type II integral membrane protein (NKG2D)Biología celular (Biología)Bioquímica (Biología)InmunologíaGenética2403 Bioquímica2407 Biología Celular2412 Inmunología2415 Biología Molecular