TY - JOUR
T1 - Regulation of natural cytotoxicity receptors by heparan sulfate proteoglycans in -cis
T2 - A lesson from NKp44
AU - Brusilovsky, Michael
AU - Radinsky, Olga
AU - Cohen, Limor
AU - Yossef, Rami
AU - Shemesh, Avishai
AU - Braiman, A.
AU - Mandelboim, Ofer
AU - Campbell, Kerry S.
AU - Porgador, Angel
N1 - Publisher Copyright:
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2015/4/1
Y1 - 2015/4/1
N2 - NKp44 (NCR2) is a distinct member of natural cytotoxicity receptors (NCRs) family that can induce cytokine production and cytolytic activity in human NK cells. Heparan sulfate proteoglycans (HSPGs) are differentially expressed in various normal and cancerous tissues. HSPGs were reported to serve as ligands/co-ligands for NKp44 and other NCRs. However, HSPG expression is not restricted to either group and can be found also in NK cells. Our current study reveals that NKp44 function can be modulated through interactions with HSPGs on NK cells themselves in -cis rather than on target cells in -trans. The intimate interaction of NKp44 and the NK cell-associated HSPG syndecan-4 (SDC4) in -cis can directly regulate membrane distribution of NKp44 and constitutively dampens the triggering of the receptor. We further demonstrate, that the disruption of NKp44 and SDC4 interaction releases the receptor to engage with its ligands in -trans and therefore enhances NKp44 activation potential and NK cell functional response.
AB - NKp44 (NCR2) is a distinct member of natural cytotoxicity receptors (NCRs) family that can induce cytokine production and cytolytic activity in human NK cells. Heparan sulfate proteoglycans (HSPGs) are differentially expressed in various normal and cancerous tissues. HSPGs were reported to serve as ligands/co-ligands for NKp44 and other NCRs. However, HSPG expression is not restricted to either group and can be found also in NK cells. Our current study reveals that NKp44 function can be modulated through interactions with HSPGs on NK cells themselves in -cis rather than on target cells in -trans. The intimate interaction of NKp44 and the NK cell-associated HSPG syndecan-4 (SDC4) in -cis can directly regulate membrane distribution of NKp44 and constitutively dampens the triggering of the receptor. We further demonstrate, that the disruption of NKp44 and SDC4 interaction releases the receptor to engage with its ligands in -trans and therefore enhances NKp44 activation potential and NK cell functional response.
KW - Binding Sites/genetics
KW - Cell Line, Tumor
KW - Cytokines/biosynthesis
KW - Heparan Sulfate Proteoglycans/metabolism
KW - Humans
KW - Killer Cells, Natural/immunology
KW - Natural Cytotoxicity Triggering Receptor 2/metabolism
KW - Neoplasms/immunology
KW - Protein Binding/immunology
KW - Receptors, Immunologic/immunology
KW - Syndecan-4/metabolism
UR - http://www.scopus.com/inward/record.url?scp=84927033865&partnerID=8YFLogxK
U2 - 10.1002/eji.201445177
DO - 10.1002/eji.201445177
M3 - Article
C2 - 25546090
SN - 0014-2980
VL - 45
SP - 1180
EP - 1191
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 4
ER -