Selective Induction of Expression of a Ligand for the NKG2D Receptor by Proteasome Inhibitors

Valés‐Gómez, Mar; Chisholm, Susan E.; Cassady-Cain, Robin L.; Roda-Navarro, Pedro; Reyburn, Hugh

doi:10.1158/0008-5472.can-07-2973

Cited by 88 publications

(80 citation statements)

References 49 publications

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“…In addition, it has been reported that proteasome inhibitor treatment leads to a higher sensitivity to NK-cell-mediated killing by upregulation of ULBP2 expression [22], supporting its potential relevance in the development of anticancer therapy. We next evaluate whether NKG2D/ULBP2 interaction exerted similar effects than NKG2D cross-linking and found that activation of NKG2D receptor with platebound ULBP2 efficiently inhibited NK-cell migration (*p < 0.05; Fig.…”

Section: Nkg2d and Nkg2a Ligation Rescues Impaired Migrationmentioning

confidence: 90%

Wiskott‐Aldrich syndrome protein (WASp) and N‐WASp are involved in the regulation of NK‐cell migration upon NKG2D activation

2012

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NKG2D is a transmembrane receptor mainly expressed on CD8 + T cells and NK cells. Engagement of NKG2D with its ligands can trigger a cytotoxic response. It has beenshown that tumor cells deliver soluble NKG2D ligands as a mechanism of immune evasion through the downregulation of surface-expressed NKG2D. These ligands may be also secreted in microvesicles and regulate NK-cell function, but the existence of alternative mechanisms has not been explored. In this study, we describe that NKG2D activation inhibits NK-cell chemotaxis toward a CXCL12 gradient. Costimulation of the inhibitory receptor NKG2A rescues NK-cell migration rates. Thus, the balance of NKG2D/NKG2A activation may determine the migratory ability of NK cells. Furthermore, our data indicated that NKG2D cross-linking induces the activation of the Rho GTPases Rac1 and Cdc42, while RhoA activity is decreased. Pharmacological inhibition of the Cdc42 effectors Wiskott-Aldrich syndrome protein (WASp)/N-WASp, and the reduction of their levels using RNA interference partially abolished NKG2D-mediated impairment of cell migration, suggesting a pivotal role of Cdc42 in the regulation of NK-cell migration by NKG2D activation. Therefore, our results provide a new mechanism that may contribute to the immune response or evasion in tumors.Keywords: Chemotaxis r Migration r NKG2D r Rho GTPases r WASp Introduction NK cells are the first host defense against viral infections and tumors. Degranulation and secretion of cytokines and cytotoxic molecules are the main NK-cell functions. The outcome of NKcell activity is regulated by a balance between activating and inhibitory signals delivered by a repertoire of surface receptors. In human NK cells, these receptors may be classified in killer cell immunoglobulin-like receptors (KIR), natural cytotoxic receptors (NCRs), or C-type lectin receptors [1][2][3]. NKG2D is a C-type lectin Correspondence: Dr. Carlos López-Larrea e-mail: inmuno@hca.es activating receptor which is expressed not only in NK cells, acting as an activating receptor itself, but also in γδ T, CD8 + αβ T lymphocytes and NKT cells in humans, where it acts as a costimulatory molecule [4,5].In humans, the ligands for NKG2D (NKG2DL) are major histocompatibility class I-related chain A/B (MICA/B) and UL-16 binding proteins 1-5 (ULBP1-5) [6]. NKG2D surface levels are regulated by these ligands. In fact, NKG2DL expression may result in immune activation or immune evasion. Although ligand expression is normally restricted under physiological conditions, * These authors have equally contributed to this work.www.eji-journal.eu Eur. J. Immunol. 2012. 42: 2142-2151 Leukocyte signaling 2143it is increased in a broad variety of malignant diseases. High expression of MICA and ULBP2 is detected in ovarian cancer tissue and related to a poor prognosis [7]. Expression of NKG2DL on the cell surface of leukemia cells has also been described [8]. Furthermore, it has been described that the soluble forms of NKG2DL may be released from tumor cells [9,10] and that elevated levels a...

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Section: Nkg2d and Nkg2a Ligation Rescues Impaired Migrationmentioning

confidence: 90%

Wiskott‐Aldrich syndrome protein (WASp) and N‐WASp are involved in the regulation of NK‐cell migration upon NKG2D activation

2012

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“…Next we focused on posttranslational pathways important for NKG2D ligand regulation. It has been recognized that proteasomal inhibition is important for the regulation of NKG2D ligands, specifically for the induction of cell surface-expressed ULBP2 (17). Hence, we hypothesized that the different expression patterns of CH 3 SeH and FR901228 could be a result of differences in proteasome regulation.…”

Section: The Nkg2d Ligand-regulating Effect Of Ch 3 Seh and An Hdac Imentioning

confidence: 97%

“…All ligands are MHC class I-related glycoproteins (6). Different forms of cellular stress result in increased NKG2D ligand surface expression, including heat shock, virus infection, inflammatory cytokines, histone deacetylase (HDAC) inhibitors, propionic acid, retinoic acid, proteasome inhibitors, Toll-like receptor (TLR) signaling, and DNA damage response (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Moreover, surface expression of NKG2D ligands on a variety of tumors derived from different origins present an attractive target for anticancer therapy (18 -20).…”

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confidence: 99%

The Selenium Metabolite Methylselenol Regulates the Expression of Ligands That Trigger Immune Activation through the Lymphocyte Receptor NKG2D

Hagemann-Jensen

Uhlenbrock

Kehlet

et al. 2014

Journal of Biological Chemistry

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Background: Immune activation through a balanced cell surface expression of human NKG2D ligands is crucial for the elimination of diseased cells. Results: Methylselenol induces the expression of the NKG2D ligands MICA/B but specifically inhibits ULBP2 protein expression. Conclusion: Methylselenol regulates NKG2D ligand expression on transcriptional and posttranscriptional levels. Significance: Methylselenol is the first identified metabolite that diversely regulates NKG2D ligands, and, therefore, its implementation could improve NKG2D-based immune therapy.

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“…6 Recruitment to detergent-resistant membranes is a mechanism described for incorporation of proteins into exosomes (40); thus, why would ULBP3 but not ULBP2 be preferentially included into exosomes? We hypothesized that ULBP2 is not excluded from exosomes but rather is more susceptible to metalloprotease attack and is therefore lost by proteolysis before inclusion into exosomes.…”

Section: Differential Kinetics and Shedding Of Ulbp1 -2 And -3-tomentioning

confidence: 99%

“…In general, NKG2D-L are not expressed ubiquitously; instead, they are expressed in response to several types of cellular stress, such as pathogen infection (4), DNA damage (5), proteasome inhibition (6), and tumor transformation (7). For example, MICA/B are expressed in epithelial tumors, melanoma, neuroblastoma, various hematopoietic malignancies, and carcinomas; ULBPs are found in leukemia, gliomas and melanomas.…”

mentioning

confidence: 99%

Differential Mechanisms of Shedding of the Glycosylphosphatidylinositol (GPI)-anchored NKG2D Ligands

Fernández-Messina

Ashiru

Boutet

et al. 2010

Journal of Biological Chemistry

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141

166

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Tumor cells release NKG2D ligands to evade NKG2D-mediated immune surveillance. The purpose of our investigation was to explore the cellular mechanisms of release used by various members of the ULBP family. Using biochemical and cellular approaches in both transfectant systems and tumor cell lines, this paper shows that ULBP1, ULBP2, and ULBP3 are released from cells with different kinetics and by distinct mechanisms. Whereas ULBP2 is mainly shed by metalloproteases, ULBP3 is abundantly released as part of membrane vesicles known as exosomes. Interestingly, exosomal ULBP3 protein is much more potent for down-modulation of the NKG2D receptor than soluble ULBP2 protein. This is the first report showing functionally relevant differences in the biochemistry of the three members of the ULBP family and confirms that in depth study of the biochemical features of individual NKG2D ligands will be necessary to understand and manipulate the biology of these proteins for therapy.NKG2D is an activating immune receptor that can be expressed by most cytotoxic lymphocytes, including NK and CD8ϩ T cells (1). Engagement of NKG2D by its ligands leads to the activation or co-stimulation of lysis and cytokine secretion (for review, see Ref. 2). In humans, NKG2D ligands (NKG2D-L) 5 occur in two families of proteins: the polymorphic family of MHC-I-related chain A/B (MICA/B) and the multigene family of UL16-binding proteins (ULBPs, also known as RAET1A-E). In total, 10 members of this gene family have been described, of which six can be expressed as functional proteins (3). Two members of the ULBP family have a transmembrane region (ULBP4 and -5), like MICA/B, whereas the other ULBP molecules are linked to the cell membrane via glycosylphosphatidylinositol (GPI) anchors. The existence of such a large number of ligands for a single receptor is not fully understood but may reflect a differential role for different ligands in immune surveillance or an evolutionary response to selective pressures exerted by pathogens or cancer.In general, NKG2D-L are not expressed ubiquitously; instead, they are expressed in response to several types of cellular stress, such as pathogen infection (4), DNA damage (5), proteasome inhibition (6), and tumor transformation (7). For example, MICA/B are expressed in epithelial tumors, melanoma, neuroblastoma, various hematopoietic malignancies, and carcinomas; ULBPs are found in leukemia, gliomas and melanomas. An additional complication is that mRNA can be found in many cells that do not express protein suggesting post-transcriptional regulation of NKG2D-L expression (8 -10).Mice deficient in NKG2D expression show an enhanced susceptibility to the development of tumors (11). However, shedding NKG2D-L as soluble molecules allows tumor cells to evade NKG2D surveillance. Apart from reducing NKG2D-L expression on the tumor cell surface, the release of soluble molecules may also impair immune surveillance by promoting down-regulation of NKG2D (12, 13). In fact, the sustained presence in vivo of NKG2D-L down-modulates...

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Selective Induction of Expression of a Ligand for the NKG2D Receptor by Proteasome Inhibitors

Abstract: The interaction of the activating receptor NKG2D with its ligands plays an important role in immunosurveillance of tumors and infectious pathogens, but dysregulation of this system may lead to autoimmunity.

Cited by 88 publications

References 49 publications

Wiskott‐Aldrich syndrome protein (WASp) and N‐WASp are involved in the regulation of NK‐cell migration upon NKG2D activation

Wiskott‐Aldrich syndrome protein (WASp) and N‐WASp are involved in the regulation of NK‐cell migration upon NKG2D activation

The Selenium Metabolite Methylselenol Regulates the Expression of Ligands That Trigger Immune Activation through the Lymphocyte Receptor NKG2D

Differential Mechanisms of Shedding of the Glycosylphosphatidylinositol (GPI)-anchored NKG2D Ligands

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