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c-Cbl regulates MICA- but not ULBP2-induced NKG2D down-modulation in human NK cells.
Eur J Immunol. 2014 Sep; 44(9):2761-70.EJ

Abstract

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.

Authors+Show Affiliations

Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24846123

Citation

Molfetta, Rosa, et al. "C-Cbl Regulates MICA- but Not ULBP2-induced NKG2D Down-modulation in Human NK Cells." European Journal of Immunology, vol. 44, no. 9, 2014, pp. 2761-70.
Molfetta R, Quatrini L, Capuano C, et al. C-Cbl regulates MICA- but not ULBP2-induced NKG2D down-modulation in human NK cells. Eur J Immunol. 2014;44(9):2761-70.
Molfetta, R., Quatrini, L., Capuano, C., Gasparrini, F., Zitti, B., Zingoni, A., Galandrini, R., Santoni, A., & Paolini, R. (2014). C-Cbl regulates MICA- but not ULBP2-induced NKG2D down-modulation in human NK cells. European Journal of Immunology, 44(9), 2761-70. https://doi.org/10.1002/eji.201444512
Molfetta R, et al. C-Cbl Regulates MICA- but Not ULBP2-induced NKG2D Down-modulation in Human NK Cells. Eur J Immunol. 2014;44(9):2761-70. PubMed PMID: 24846123.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - c-Cbl regulates MICA- but not ULBP2-induced NKG2D down-modulation in human NK cells. AU - Molfetta,Rosa, AU - Quatrini,Linda, AU - Capuano,Cristina, AU - Gasparrini,Francesca, AU - Zitti,Beatrice, AU - Zingoni,Alessandra, AU - Galandrini,Ricciarda, AU - Santoni,Angela, AU - Paolini,Rossella, Y1 - 2014/06/17/ PY - 2014/01/29/received PY - 2014/04/14/revised PY - 2014/05/12/accepted PY - 2014/5/22/entrez PY - 2014/5/23/pubmed PY - 2014/11/11/medline KW - Endocytosis KW - NK cells KW - NKG2D ligands KW - NKG2D receptor SP - 2761 EP - 70 JF - European journal of immunology JO - Eur. J. Immunol. VL - 44 IS - 9 N2 - 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. SN - 1521-4141 UR - https://www.unboundmedicine.com/medline/citation/24846123/c_Cbl_regulates_MICA__but_not_ULBP2_induced_NKG2D_down_modulation_in_human_NK_cells_ L2 - https://doi.org/10.1002/eji.201444512 DB - PRIME DP - Unbound Medicine ER -