c-Cbl regulates MICA- but not ULBP2-induced NKG2D down-modulation in human NK cells.
The NKG2D activating receptor on human NK cells mediates "altered self" recognition, as its ligands (NKG2DLs) are upregulated on target cells in a variety of stress conditions. Evidence collected in the past years shows that, even though expression of NKG2DLs acts as a danger signal that renders tumor cells susceptible to cytotoxicity, chronic exposure to soluble or membrane-bound NKG2DLs can lead to down-modulation of receptor expression and impairment of NKG2D-mediated cell functions. Here, we evaluated whether different cell-bound NKG2DLs, namely MICA and ULBP2, are equivalently able to induce NKG2D down-modulation on human NK cells. We found that although both ligands reduce NKG2D surface expression, MICA promotes a stronger receptor down-modulation than ULBP2, leading to a severe impairment of NKG2D-dependent NK-cell cytotoxicity. We also provide evidence that the ubiquitin pathway and c-Cbl direct MICA-induced but not ULBP2-induced NKG2D internalization and degradation, thus identifying a molecular mechanism to explain the differential effects of MICA and ULBP2 on NKG2D expression. A better understanding of the molecular mechanisms employed by the different NKG2DLs to control NKG2D surface expression could be useful for the development of anti-tumor strategies to restore a normal level of NKG2D receptors on human NK cells.
Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.
Rosa
R
Molfetta
Linda
L
Quatrini
Cristina
C
Capuano
Francesca
F
Gasparrini
Beatrice
B
Zitti
Alessandra
A
Zingoni
Ricciarda
R
Galandrini
Angela
A
Santoni
Rossella
R
Paolini
D002460:Cell Line; D015536:Down-Regulation / Q000276:immunology*; D058851:GPI-Linked Proteins / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology*; D059748:Proteolysis; D050721:Proto-Oncogene Proteins c-cbl / Q000276:immunology*; D025801:Ubiquitin / Q000276:immunology
D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; C423230:ULBP2 protein, human; D025801:Ubiquitin; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human
Endocytosis; NK cells; NKG2D ligands; NKG2D receptor