Differential mechanisms of shedding of the glycosylphosphatidylinositol (GPI)-anchored NKG2D ligands.
Tumor cells release NKG2D ligands to evade NKG2D-mediated immune surveillance. The purpose of our investigation was to explore the cellular mechanisms of release used by various members of the ULBP family. Using biochemical and cellular approaches in both transfectant systems and tumor cell lines, this paper shows that ULBP1, ULBP2, and ULBP3 are released from cells with different kinetics and by distinct mechanisms. Whereas ULBP2 is mainly shed by metalloproteases, ULBP3 is abundantly released as part of membrane vesicles known as exosomes. Interestingly, exosomal ULBP3 protein is much more potent for down-modulation of the NKG2D receptor than soluble ULBP2 protein. This is the first report showing functionally relevant differences in the biochemistry of the three members of the ULBP family and confirms that in depth study of the biochemical features of individual NKG2D ligands will be necessary to understand and manipulate the biology of these proteins for therapy.
Fernández-Messina
Lola
L
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom.
Ashiru
Omodele
O
Boutet
Philippe
P
Agüera-González
Sonia
S
Skepper
Jeremy N
JN
Reyburn
Hugh T
HT
Valés-Gómez
Mar
M
D000818:Animals; D001671:Biochemistry / Q000379:methods; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D055354:Exosomes / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D058851:GPI-Linked Proteins; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D006801:Humans; D007107:Immune System; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008954:Models, Biological; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*
D058851:GPI-Linked Proteins; D017261:Glycosylphosphatidylinositols; D036341:Intercellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; C423229:ULBP3 protein, human