Glycosyl-Phosphatidyl-Inositol (GPI)-Anchors and Metalloproteases: Their Roles in the Regulation of Exosome Composition and NKG2D-Mediated Immune Recognition.
Communication within the immune system depends on the release of factors that can travel and transmit information at points distant from the cell that produced them. In general, immune cells use two key strategies that can occur either at the plasma membrane or in intracellular compartments to produce such factors, vesicle release and proteolytic cleavage. Release of soluble factors in exosomes, a subset of vesicles that originate from intracellular compartments, depends generally on biochemical and lipid environment features. This physical environment allows proteins to be recruited to membrane microdomains that will be later endocytosed and further released to the extracellular milieu. Cholesterol and sphingolipid rich domains (also known as lipid rafts or detergent-resistant membranes, DRMs) often contribute to exosomes and these membrane regions are rich in proteins modified with Glycosyl-Phosphatidyl-Inositol (GPI) and lipids. For this reason, many palmitoylated and GPI-anchored proteins are preferentially recruited to exosomes. In this review, we analyse the biochemical features involved in the release of NKG2D-ligands as an example of functionally related gene families encoding both transmembrane and GPI-anchored proteins that can be released either by proteolysis or in exosomes, and modulate the intensity of the immune response. The immune receptor NKG2D is present in all human Natural Killer and T cells and plays an important role in the first barrier of defense against tumor and infection. However, tumor cells can evade the immune system by releasing NKG2D-ligands to induce down-regulation of the receptor. Some NKG2D-ligands can be recruited to exosomes and potently modulate receptor expression and immune function, while others are more susceptible to metalloprotease cleavage and are shed as soluble molecules. Strikingly, metalloprotease inhibition is sufficient to drive the accumulation in exosomes of ligands otherwise released by metalloprotease cleavage. In consequence, NKG2D-ligands appear as different entities in different cells, depending on cellular metabolism and biochemical structure, which mediate different intensities of immune modulation. We discuss whether similar mechanisms, depending on an interplay between metalloprotease cleavage and exosome release, could be a more general feature regulating the composition of exosomes released from human cells.
Department of Immunology and Oncology, Spanish National Centre for Biotechnology Madrid, Spain.
Sheila
S
López-Cobo
Department of Immunology and Oncology, Spanish National Centre for Biotechnology Madrid, Spain.
Carmen
C
Campos-Silva
Department of Immunology and Oncology, Spanish National Centre for Biotechnology Madrid, Spain.
Mar
M
Valés-Gómez
DRMs; GPI-anchored proteins; MICA/B; ULBP; exosomes; immune evasion; metalloproteases; shedding
J Biol Chem. 2011 Apr 22;286(16):14383-95
21300796
Biochem J. 2004 May 15;380(Pt 1):161-71
14965343
J Biol Chem. 2003 Mar 28;278(13):10963-72
12519789
Curr Top Membr. 2015;75:269-303
26015286
Biochim Biophys Acta. 2016 Apr;1858(4):632-9
26706096
Genes Immun. 2015 Jan-Feb;16(1):71-82
25393931
Int J Cancer. 2009 Apr 1;124(7):1594-604
19089914
BMC Cancer. 2011 May 23;11:194
21605422
Eur J Immunol. 2009 Nov;39(11):3207-16
19658097
J Biol Chem. 1997 Jul 4;272(27):17216-22
9202045
Tissue Antigens. 2015 Jun;85(6):476-83
25871737
J Immunol. 2009 May 15;182(10):6600-9
19414815
Proc Jpn Acad Ser B Phys Biol Sci. 2014;90(4):130-43
24727937
Cancer Res. 2012 Jan 15;72 (2):460-71
22102694
Cell. 1990 Apr 20;61(2):361-70
2158863
Mol Membr Biol. 2006 Jan-Feb;23(1):89-99
16611584
Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6259-63
8022771
Cancer Res. 2009 Oct 15;69(20):8050-7
19826051
Clin Immunol. 2013 Dec;149(3):432-9
24211717
Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9683-8
15210972
J Immunol. 2009 Jan 1;182(1):49-53
19109134
J Biol Chem. 2006 Feb 10;281(6):3157-64
16332693
Placenta. 2011 Dec;32(12 ):975-80
22018416
Nucleic Acids Res. 2012 Jan;40(Database issue):D1241-4
21989406
Curr Biol. 2009 Dec 1;19(22):1875-85
19896381
Mol Cell Proteomics. 2015 Nov;14 (11):3015-22
26272980
Nat Immunol. 2001 Mar;2(3):255-60
11224526
Tissue Antigens. 1997 May;49(5):448-54
9174136
J Immunol. 2002 Oct 15;169(8):4098-102
12370336
Biochem J. 2013 Sep 1;454(2):295-302
23772752
Org Biomol Chem. 2015 Oct 14;13(38):9775-82
26264754
Trends Immunol. 2008 Aug;29(8):397-403
18602338
Oncoimmunology. 2014 Apr 25;3:e28497
25050215
J Immunol. 2004 Jul 15;173(2):1078-84
15240696
Exp Cell Res. 2006 Dec 10;312(20):3969-80
17010968
FASEB J. 2013 Jun;27(6):2440-50
23395909
Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1297-302
14745008
Hepatology. 2010 Apr;51(4):1264-73
20099300
Am J Neurodegener Dis. 2012;1(1):15-31
23383379
Cancer Res. 2005 Dec 1;65(23):11136-45
16322264
Cancer Res. 2005 Jul 15;65(14):6321-9
16024634
J Immunol. 2010 Apr 1;184(7):3346-50
20208009
Cell Signal. 2009 Feb;21(2):324-38
19010410
Blood Cells Mol Dis. 2005 Sep-Oct;35(2):116-21
16023874
J Immunol. 2006 Jun 15;176(12):7385-93
16751383
Cancer Sci. 2008 Jun;99(6):1279-86
18422748
Front Biosci. 2008 May 01;13:3448-56
18508446
Immunol Cell Biol. 2016 May;94(5):479-85
26732147
Reprod Biol Endocrinol. 2013 Jan 15;11:2
23320481
Biochim Biophys Acta. 2013 Jul;1831(7):1302-9
24046871
J Extracell Vesicles. 2013 Dec 23;2:null
24371518
Invest Ophthalmol Vis Sci. 2015 Aug;56(9):5323-9
25015352
Biochim Biophys Acta. 2013 Nov;1833(11):2473-8
23380706
Curr Immunol Rev. 2009 Feb;5(1):22-34
19626129
Eur J Immunol. 2003 Feb;33(2):522-31
12645951
Eur J Immunol. 2011 Dec;41(12):3667-76
21928280
J Immunol. 2009 Jan 1;182(1):39-43
19109132
Nat Immunol. 2006 May;7(5):524-32
16582911
Mol Med Rep. 2013 Mar;7(3):991-7
23314034
J Immunol. 2014 Aug 1;193(3):1344-52
24973455
Nature. 1997 Jun 5;387(6633):569-72
9177342
J Immunol. 1997 Dec 1;159(11):5648-53
9548508
J Immunol. 2002 Nov 15;169(10):5377-81
12421908
Front Immunol. 2012 Sep 25;3:299
23056001
Oncogene. 2008 Oct 6;27(45):5944-58
18836475
Front Immunol. 2015 Apr 27;6:193
25964786
Cell Biol Int. 2011 Jun;35(6):569-74
21143201
Front Pharmacol. 2012 Jul 17;3:140
22822400
Cancer Res. 2006 Mar 1;66(5):2520-6
16510567
J Immunol. 2009 Apr 15;182(8):4800-8
19342658
Cancer Immun. 2013 May 01;13:8
23833565
J Biol Chem. 2015 Oct 23;290(43):26059-71
26359498
Immunity. 2001 Jul;15(1):83-93
11485740
Tumour Biol. 2016 Apr;37(4):5455-66
26563374
J Biol Chem. 2009 Aug 21;284(34):22590-600
19564338
Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12445-50
8901601
Curr Opin Cell Biol. 2001 Aug;13(4):470-7
11454454
Immunity. 2001 Feb;14(2):123-33
11239445
Biochem Biophys Res Commun. 2003 May 23;305(1):129-35
12732206
BMB Rep. 2015 May;48(5):277-82
25208722
Int J Oncol. 2011 Dec;39(6):1491-9
21805029
Blood. 2003 Dec 15;102(13):4336-44
12881314
Oncol Rep. 2012 Nov;28(5):1585-90
22923031
Nature. 2002 Oct 17;419(6908):734-8
12384702
PLoS One. 2015 Mar 23;10(3):e0121184
25798862
Annu Rev Immunol. 2013;31:413-41
23298206
J Clin Invest. 2004 Aug;114(4):560-8
15314693
PLoS Biol. 2012;10(12):e1001450
23271954
Science. 1999 Jul 30;285(5428):727-9
10426993
Prion. 2012 Nov-Dec;6(5):498-509
23093798
Scand J Immunol. 2013 Aug;78(2):120-9
23679194
Cancer Res. 2008 Aug 1;68(15):6368-76
18676862
Biochem J. 2006 Feb 1;393(Pt 3):609-18
16229685
Expert Rev Proteomics. 2011 Apr;8(2):263-77
21501018
Cancer Res. 2010 Jan 15;70(2):481-9
20068167
Anticancer Res. 2014 Aug;34(8):4529-38
25075096
Annu Rev Cell Dev Biol. 2014;30:255-89
25288114
Science. 2015 Apr 3;348(6230):136-9
25745066
J Immunol. 2009 Jul 1;183(1):340-51
19542445
Anticancer Res. 2011 Jul;31(7):2505-10
21873167
J Biol Chem. 2010 Nov 26;285(48):37531-41
20876574
J Cell Sci. 2011 Feb 1;124(Pt 3):321-7
21224393
J Immunol. 2012 Aug 1;189(3):1360-71
22730533
J Biol Chem. 2010 Mar 19;285(12):8543-51
20080967
Cytokine. 1992 Mar;4(2):96-100
1633265
Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1298-303
9037047
Cancer Res. 2008 Mar 1;68(5):1546-54
18316620
J Biol Chem. 2010 May 28;285(22):16408-15
20304922