Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Carrier Proteins / immunology
-
Carrier Proteins / metabolism*
-
Down-Regulation*
-
Histocompatibility Antigens Class I / immunology
-
Histocompatibility Antigens Class I / metabolism*
-
Humans
-
Immunoglobulins / immunology
-
Ligands
-
Lysosomes / metabolism
-
Membrane Glycoproteins / metabolism*
-
Membrane Proteins / metabolism
-
Mice
-
Mice, Inbred BALB C
-
Minor Histocompatibility Antigens / immunology
-
Minor Histocompatibility Antigens / metabolism*
-
Muromegalovirus / metabolism*
-
Muromegalovirus / physiology
-
NIH 3T3 Cells
-
NK Cell Lectin-Like Receptor Subfamily K
-
Protein Processing, Post-Translational
-
Protein Structure, Tertiary
-
Receptors, Fc / metabolism*
-
Receptors, Immunologic / immunology
-
Receptors, Immunologic / metabolism*
-
Receptors, Natural Killer Cell
-
Viral Proteins / metabolism*
-
Virus Replication / physiology
Substances
-
Carrier Proteins
-
Fcr-1 protein, Mouse cytomegalovirus 1
-
Histocompatibility Antigens Class I
-
Immunoglobulins
-
KLRK1 protein, human
-
Klrk1 protein, mouse
-
Ligands
-
Membrane Glycoproteins
-
Membrane Proteins
-
Minor Histocompatibility Antigens
-
NK Cell Lectin-Like Receptor Subfamily K
-
Receptors, Fc
-
Receptors, Immunologic
-
Receptors, Natural Killer Cell
-
UL16 binding protein 1, mouse
-
Viral Proteins
-
minor H antigen H60