Selective intracellular retention of virally induced NKG2D ligands by the human cytomegalovirus UL16 glycoprotein.
Human cytomegalovirus (HCMV) has evolved a multitude of molecular mechanisms to evade the antiviral immune defense of the host. Recently, using soluble recombinant molecules, the HCMV UL16 glycoprotein was shown to interact with some ligands of the activating immunoreceptor NKG2D and, therefore, may also function as a viral immunomodulator. However, the role of UL16 during the course of HCMV infection remained unclear. Here, we demonstrate that HCMV infection of fibroblasts induces expression of all known NKG2D ligands (NKG2DL). However, solely MICA and ULBP3 reach the cellular surface to engage NKG2D, whereas MICB, ULBP1 and ULBP2 are selectively retained in the endoplasmic reticulum by UL16. UL16-mediated reduction of NKG2DL cell surface density diminished NK cytotoxicity. Thus, UL16 functions by capturing activating ligands for cytotoxic lymphocytes that are synthesized in response to HCMV infection.
Welte
Stefan A
SA
Department of Immunology, Institute for Cell Biology, Eberhard-Karls-University Tübingen, Tübingen, Germany.
Sinzger
Christian
C
Lutz
Stefan Z
SZ
Singh-Jasuja
Harpreet
H
Sampaio
Kerstin Laib
KL
Eknigk
Ute
U
Rammensee
Hans-Georg
HG
Steinle
Alexander
A
D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D003587:Cytomegalovirus / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000276:immunology*; D015536:Down-Regulation; D005347:Fibroblasts; D005434:Flow Cytometry; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K; D021381:Protein Transport; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D014162:Transfection; D014764:Viral Proteins / Q000276:immunology / Q000378:metabolism*
D002352:Carrier Proteins; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; C098080:MICB antigen; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C423231:ULBP1 protein, human; C423230:ULBP2 protein, human; D014764:Viral Proteins