Natural killer cell evasion by an E3 ubiquitin ligase from Kaposi's sarcoma-associated herpesvirus

2008 ◽  
Vol 36 (3) ◽  
pp. 459-463 ◽  
Author(s):  
Mair Thomas ◽  
Mark Wills ◽  
Paul J. Lehner
Keyword(s):  
Cell Surface ◽  
Natural Killer ◽  
Kaposi's Sarcoma ◽  
Nk Cell ◽  
Cytoplasmic Tail ◽  
Kaposi’S Sarcoma ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Lysine Residues ◽  
Kaposi’S Sarcoma Associated Herpesvirus

Viruses exploit the ubiquitin system by targeting cell-surface receptors recognized by immune cells for internalization, thereby evading recognition. We have characterized the KSHV (Kaposi's sarcoma-associated herpesvirus)-encoded E3 ubiquitin ligases, K3 and K5. We find their activities not only prevent recognition by cytotoxic T-lymphocytes, but also promote evasion of NK (natural killer) cells. NK cells recognize and lyse virus-infected cells expressing ligands for activatory receptors such as NKG2D (NK group 2D). K5 down-regulates cell-surface expression of the NKG2D ligands MICA/B (MHC class I-related chains A and B) by ubiquitination of MIC cytoplasmic tail lysine residues. Ubiquitination results in redistribution of MICA from the plasma membrane to an intracellular compartment, but does not result in an increased rate of degradation. Furthermore, K5 down-regulates cell-surface expression of another NK cell activatory receptor ligand, AICL (activation-induced C-type lectin). This activity requires the K5 RING (really interesting new gene)-CH domain and AICL cytoplasmic tail lysine residues. MICA and AICL down-regulation by K5 reduces NK cell-mediated cytotoxicity towards target cells, thus providing KSHV with an NK cell evasion mechanism.

Kaposi’s sarcoma-associated herpesvirus ubiquitin ligases downregulate cell surface expression of l-selectin

2021 ◽  
Vol 102 (11) ◽  
Author(s):  
Mizuho Kajikawa ◽  
Nanae Imaizumi ◽  
Shiho Machii ◽  
Tomoka Nakamura ◽  
Nana Harigane ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Immune Evasion ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Ubiquitin Ligases ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic etiological factor for Kaposi’s sarcoma and primary effusion lymphoma in immunocompromised patients. KSHV utilizes two immune evasion E3 ubiquitin ligases, namely K3 and K5, to downregulate the expression of antigen-presenting molecules and ligands of natural killer (NK) cells in the host cells through an ubiquitin-dependent endocytic mechanism. This allows the infected cells to evade surveillance and elimination by cytotoxic lymphocytes and NK cells. The number of host cell molecular substrates reported for these ubiquitin ligases is limited. The identification of novel substrates for these ligases will aid in elucidating the mechanism underlying immune evasion of KSHV. This study demonstrated that K5 downregulated the cell surface expression of l-selectin, a C-type lectin-like adhesion receptor expressed in the lymphocytes. Tryptophan residue located at the centre of the E2-binding site in the K5 RINGv domain was essential to downregulate l-selectin expression. Additionally, the lysine residues located at the cytoplasmic tail of l-selectin were required for the K5-mediated downregulation of l-selectin. K5 promoted the degradation of l-selectin through polyubiquitination. These results suggest that K5 downregulates l-selectin expression on the cell surface by promoting polyubiquitination and ubiquitin-dependent endocytosis, which indicated that l-selectin is a novel substrate for K5. Additionally, K3 downregulated l-selectin expression. The findings of this study will aid in the elucidation of a novel immune evasion mechanism in KSHV.

Impact of β2 integrin deficiency on mouse natural killer cell development and function

Blood ◽  
2011 ◽  
Vol 117 (10) ◽  
pp. 2874-2882 ◽  
Author(s):  
Karine Crozat ◽  
Céline Eidenschenk ◽  
Baptiste N. Jaeger ◽  
Philippe Krebs ◽  
Sophie Guia ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Surface Expression ◽  
Cell Maturation ◽  
Cell Surface Expression ◽  
Mcmv Infection ◽  
Β2 Integrin

Abstract Natural killer (NK) cells are innate immune cells that express members of the leukocyte β2 integrin family in humans and mice. These CD11/CD18 heterodimers play critical roles in leukocyte trafficking, immune synapse formation, and costimulation. The cell-surface expression of one of these integrins, CD11b/CD18, is also recognized as a major marker of mouse NK-cell maturation, but its function on NK cells has been largely ignored. Using N-ethyl-N-nitrosourea (ENU) mutagenesis, we generated a mouse carrying an A → T transverse mutation in the Itgb2 gene, resulting in a mutation that prevented the cell-surface expression of CD18 and its associated CD11a, CD11b, and CD11c proteins. We show that β2 integrin–deficient NK cells have a hyporesponsive phenotype in vitro, and present an alteration of their in vivo developmental program characterized by a selective accumulation of c-kit+ cells. NK-cell missing-self recognition was partially altered in vivo, whereas the early immune response to mouse cytomegalovirus (MCMV) infection occurred normally in CD18-deficient mice. Therefore, β2 integrins are required for optimal NK-cell maturation, but this deficiency is partial and can be bypassed during MCMV infection, highlighting the robustness of antiviral protective responses.

scholarly journals Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell–mediated lysis of myeloma

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1309-1317 ◽  
Author(s):  
Jumei Shi ◽  
Guido J. Tricot ◽  
Tarun K. Garg ◽  
Priyangi A. Malaviarachchi ◽  
Susann M. Szmania ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Surface Expression ◽  
Class I ◽  
Cell Surface Expression ◽  
Significant Activity

AbstractHuman leukocyte antigen class I molecules expressed by tumor cells play a central role in the regulation of natural killer (NK) cell–mediated immune responses. The proteasome inhibitor bortezomib has demonstrated significant activity in multiple myeloma (MM). We hypothesized that treatment of MM with bortezomib results in the reduction of cell-surface expression of class I and thereby sensitizes MM to NK cell–mediated lysis. Here we report that bortezomib down-regulates class I in a time- and dose-dependent fashion on all MM cell lines and patient MM cells tested. Downregulation of class I can also be induced in vivo after a single dose of 1.0 mg/m2 bortezomib. Bortezomib significantly enhances the sensitivity of patient myeloma to allogeneic and autologous NK cell–mediated lysis. Further, the level of decrease in class I expression correlates with increased susceptibility to lysis by NK cells. Clinically relevant bortezomib concentrations do not affect NK-cell function. Our findings have clear therapeutic implications for MM and other NK cell–sensitive malignancies in the context of both allogeneic and autologous adoptively transferred NK cells.

302 INHIBITION OF HUMAN NATURAL KILLER (NK) CELL-MEDIATED CYTOTOXICITY IN MINIPIG CELLS BY KAPOSI'S SARCOMA-ASSOCIATED HERPESVIRUS K5 PROTEIN

2008 ◽  
Vol 20 (1) ◽  
pp. 231
Author(s):  
G. S. Han ◽  
K. M. Choi ◽  
S. P. Hong ◽  
J. Y. Yoo ◽  
E. J. Kim ◽  
...  
Keyword(s):  
Natural Killer ◽  
Cell Lines ◽  
Kaposi's Sarcoma ◽  
Cell Activation ◽  
Nk Cell ◽  
Kaposi’S Sarcoma ◽  
Xenograft Rejection ◽  
Fetal Fibroblasts ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

Human natural killer (NK) cell-mediated response plays an important role in xenograft rejection. In the case of pig-to-human xenotransplantation, it has been suggested that NK cells are involved in delayed-type rejection, which is characterized by pig endothelial cell activation, direct lysis, and secretion of proinflammatory cytokines. Natural killer cell activation can be a direct barrier to the potential use of pig organs for human xenograft transplantation. Therefore, it is important to suppress NK cell activity on pig-to-human xenografts. Expression of Kaposi's sarcoma-associated herpesvirus (KSHV)-K5 molecules inhibits the cytotoxic activity of NK-activating receptor (B7-2, ICAM-1). As a consequence, K5 expression drastically inhibits NK cell-mediated cytotoxicity. In this study, we produced cell lines expressing K5 to control NK-mediated cytotoxicity in minipig cells. We transfected the K5 gene into minipig fetal fibroblasts and established 2 transgenic clonal cell lines. Presence of the K5 gene was confirmed by PCR, and expression of the gene was identified by real-time PCR and flow cytometry. In an NK cytotoxicity assay, the rate of NK-92MI-mediated cytotoxicity was significantly reduced, to 48.4 � 5.9% compared with the control (75.6 � 5.8%; P < 0.05, n = 8, paired t-testing). In conclusion, these results indicate that the expression of K5 molecules on porcine cells can efficiently control NK-mediated cytotoxicity. This strategy can be used in transgenic pig production in which porcine organs would be protected from NK-mediated rejection.

scholarly journals Control of immune ligands by members of a cytomegalovirus gene expansion suppresses natural killer cell activation

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Ceri A Fielding ◽  
Michael P Weekes ◽  
Luis V Nobre ◽  
Eva Ruckova ◽  
Gavin S Wilkie ◽  
...  
Keyword(s):  
Cell Surface ◽  
Natural Killer ◽  
Immune Regulation ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Gene Expansion ◽  
Proteomics Approach

The human cytomegalovirus (HCMV) US12 family consists of ten sequentially arranged genes (US12-21) with poorly characterized function. We now identify novel natural killer (NK) cell evasion functions for four members: US12, US14, US18 and US20. Using a systematic multiplexed proteomics approach to quantify ~1300 cell surface and ~7200 whole cell proteins, we demonstrate that the US12 family selectively targets plasma membrane proteins and plays key roles in regulating NK ligands, adhesion molecules and cytokine receptors. US18 and US20 work in concert to suppress cell surface expression of the critical NKp30 ligand B7-H6 thus inhibiting NK cell activation. The US12 family is therefore identified as a major new hub of immune regulation.

scholarly journals Domains of the TCR beta-chain required for early thymocyte development.

1996 ◽  
Vol 184 (5) ◽  
pp. 1833-1843 ◽  
Author(s):  
H Jacobs ◽  
J Iacomini ◽  
M van de Ven ◽  
S Tonegawa ◽  
A Berns
Keyword(s):  
Cell Surface ◽  
Cytoplasmic Tail ◽  
Cell Receptor ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Beta Chain ◽  
Thymocyte Development ◽  
Developmental Transition ◽  
T Cell Receptor Beta ◽  
Thymocyte Differentiation

The T cell receptor beta (TCR beta) chain controls the developmental transition from CD4-CD8- to CD4+8+thymocytes. We show that the extracellular constant region and the transmembrane region, but not the variable domain or cytoplasmic tail of the TCR beta chain are required for this differentiation step. TCR beta mutant chains lacking the cytoplasmic tail can be found at the cell surface both in functional TCR/CD3 complexes and in a GPI-anchored monomeric form indicating that the cytoplasmic tail of the TCR beta chain functions as an ER retention signal. The concordance between cell surface expression of the mutant chains as TCR/CD3 complexes and their capacity to mediate thymocyte differentiation supports the CD3 mediated feedback model in which preTCR/CD3 complexes control the developmental transition from CD4-CD8- to CD4+CD8+thymocytes.

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