The herpesviral Fc receptor fcr-1 down-regulates the NKG2D ligands MULT-1 and H60.
Members of the alpha- and beta-subfamily of herpesviridae encode glycoproteins that specifically bind to the Fc part of immunoglobulin (Ig)G. Plasma membrane resident herpesviral Fc receptors seem to prevent virus-specific IgG from activating antibody-dependent effector functions. We show that the mouse cytomegalovirus (MCMV) molecule fcr-1 promotes a rapid down-regulation of NKG2D ligands murine UL16-binding protein like transcript (MULT)-1 and H60 from the cell surface. Deletion of the m138/fcr-1 gene from the MCMV genome attenuates viral replication to natural killer (NK) cell response in an NKG2D-dependent manner in vivo. A distinct N-terminal module within the fcr-1 ectodomain in conjunction with the fcr-1 transmembrane domain was required to dispose MULT-1 to degradation in lysosomes. In contrast, down-modulation of H60 required the complete fcr-1 ectodomain, implying independent modes of fcr-1 interaction with the NKG2D ligands. The results establish a novel viral strategy for down-modulating NK cell responses and highlight the impressive diversity of Fc receptor functions.
Lenac
Tihana
T
Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia.
Budt
Matthias
M
Arapovic
Jurica
J
Hasan
Milena
M
Zimmermann
Albert
A
Simic
Hrvoje
H
Krmpotic
Astrid
A
Messerle
Martin
M
Ruzsics
Zsolt
Z
Koszinowski
Ulrich H
UH
Hengel
Hartmut
H
Jonjic
Stipan
S
D000818:Animals; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism*; D015536:Down-Regulation; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology; D008024:Ligands; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D015778:Minor Histocompatibility Antigens / Q000276:immunology / Q000378:metabolism*; D018146:Muromegalovirus / Q000378:metabolism* / Q000502:physiology; D041681:NIH 3T3 Cells; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011961:Receptors, Fc / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D014764:Viral Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology
D002352:Carrier Proteins; C110265:Fcr-1 protein, Mouse cytomegalovirus 1; D015395:Histocompatibility Antigens Class I; D007136:Immunoglobulins; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011961:Receptors, Fc; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C468260:UL16 binding protein 1, mouse; D014764:Viral Proteins; C114735:minor H antigen H60