Ubiquitylation of an Internalized Killer Cell Ig-Like Receptor by Triad3A Disrupts Sustained NF-κB Signaling

Miah, S. M. Shahjahan; Purdy, Amanda K.; Rodin, Nicholas B.; Macfarlane, Alexander W.; Oshinsky, Jennifer; Alvarez-Arias, Diana A.; Campbell, Kerry S.

doi:10.4049/jimmunol.1000112

Cited by 21 publications

(21 citation statements)

References 42 publications

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“…Negative regulation of KIR2DL4 signaling occurs through a different ubiquitin ligase, Triad3A that binds the cytoplasmic tail of KIR2DL4 and promotes its degradation. 51 Thus, endosomal signaling by KIR2DL4 offers the advantage of sustained signals for the secretion response that involves the secretion of cytokines and chemokines, such as IFN-c, TNF-a, IL-1a, IL-1b, IL-6 and IL-8. 47 Signaling from intracellular endosomal compartments offers the advantage of escaping the regulation by inhibitory NK receptors at the NK cell surface.…”

Section: Kir2dl4-hla-g Interactions and Endosomal Signalingmentioning

confidence: 99%

HLA-G-mediated NK cell senescence promotes vascular remodeling: implications for reproduction

Rajagopalan

2014

Cell Mol Immunol

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The uterus in early pregnancy is a non-lymphoid organ that is enriched in natural killer (NK) cells. Studies to address the role of these abundant human NK cells at the maternal/fetal interface have focused on their response to the major histocompatibility complex (MHC) molecules on fetal trophoblast cells that they contact. The interaction of maternal NK cell receptors belonging to the killer cell immunoglobulin-like receptor (KIR) family with trophoblast MHC class I molecules in pregnancy can regulate NK cell activation for secretion of pro-angiogenic factors that promote placental development. This review will cover the role of KIR at the maternal/fetal interface and focus on KIR2DL4, a KIR family member that is uniquely poised to play a role in pregnancy due to the restricted expression of its ligand, human leukocyte antigen (HLA)-G, by fetal trophoblast cells early in pregnancy. The pathways by which KIR2DL4-HLA-G interactions induce the cellular senescence of NK cells and the role of the resulting senescence-associated secretory phenotype (SASP) in vascular remodeling will be discussed in the context of reproduction.

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Section: Kir2dl4-hla-g Interactions and Endosomal Signalingmentioning

confidence: 99%

HLA-G-mediated NK cell senescence promotes vascular remodeling: implications for reproduction

Rajagopalan

2014

Cell Mol Immunol

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“…Triad3A promotes polyubiquitylation and degradation of 2DL4 (15). To compare the effects of TRAF6 and Triad3A on 2DL4-mediated signaling, both were silenced in parallel (Fig.…”

Section: Resultsmentioning

confidence: 99%

TNFR-Associated Factor 6 and TGF-β–Activated Kinase 1 Control Signals for a Senescence Response by an Endosomal NK Cell Receptor

Rajagopalan

Lee

DuPrie

et al. 2014

The Journal of Immunology

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The endosomal innate receptor CD158d (KIR2DL4) induces cellular senescence in human NK cells in response to soluble ligand (HLA-G or agonist antibody). These senescent NK cells display a senescence-associated secretory phenotype (SASP) and their secretome promotes vascular remodeling and angiogenesis. To understand how CD158d initiates signaling for a senescence response, we mapped the region in its cytoplasmic tail that controls signaling. We identified a conserved TRAF6 binding motif, which was required for CD158d-induced NF-κB activation and IL-8 secretion, for TRAF6 association with CD158d, and for TRAF6 recruitment to CD158d+ endosomes in transfected cells. The adaptor TRAF6 is known to couple proximal signals from receptors such as endosomal TLRs and CD40 through the kinase TAK1 for NF-κB-dependent pro-inflammatory responses. siRNA-mediated silencing of TRAF6 and TAK1, and inhibition of TAK1 blocked CD158d-dependent IL-8 secretion. Stimulation of primary, resting NK cells with soluble Ab to CD158d induced TRAF6 association with CD158d, induced TAK1 phosphorylation, and inhibition of TAK1 blocked the CD158d-dependent reprogramming of NK cells that produces the SASP signature. Our results reveal that a prototypic TLR and TNF-receptor signaling pathway is used by a killer cell immunoglobulin-like receptor that promotes secretion of pro-inflammatory and pro-angiogenic mediators as part of a unique senescence phenotype in NK cells.

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“…In that report, 3DL1 internalization was also observed upon binding with CpG DNA, although to a lesser extent than KIR3DL2. Furthermore, KIR2DL4, a unique activating receptor that contains a single ITIM (49), can also internalize to early endosomes, where it can mediate intracellular signaling or be degraded following ubiquitylation (13, 25). Published data, however, suggest that internalization of KIR2DL4 is independent of the transmembrane and cytoplasmic domains, since a chimeric receptor consisting of the extracellular domain of KIR2DL4 and transmembrane/cytoplasmic domains of the plasma membrane-localized gp49B receptor was also targeted to endosomes (50).…”

Section: Discussionmentioning

confidence: 99%

“…KHYG-1, NKL, Jurkat, HEK-293T and LentiX 293T (Clontech, Mountain View, CA) cells were cultured as described (8, 25, 26). Healthy volunteer blood donors were recruited by informed consent as approved by the Fox Chase Cancer Center (FCCC) Institutional Review Board.…”

Section: Methodsmentioning

confidence: 99%

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The AP-2 Clathrin Adaptor Mediates Endocytosis of an Inhibitory Killer Cell Ig-like Receptor in Human NK Cells

Purdy

Arias

Oshinsky

et al. 2014

The Journal of Immunology

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Stable surface expression of human inhibitory killer cell immunoglobulin-like receptors (KIR) is critical for controlling NK cell function and maintaining NK cell tolerance toward normal MHC-I+ cells. Our recent experiments, however, have found that antibody-bound KIR3DL1 (3DL1) readily leaves the cell surface and undergoes endocytosis to early/recycling endosomes and subsequently to late endosomes. We found that 3DL1 internalization is at least partially mediated by an interaction between the μ2 subunit of the AP-2 clathrin adaptor complex and ITIM tyrosine residues in the cytoplasmic domain of 3DL1. Disruption of the 3DL1/μ2 interaction, either by mutation of the ITIM tyrosines in 3DL1 or mutation of μ2, significantly diminished endocytosis and increased surface expression of 3DL1 in human primary NK cells and cell lines. Furthermore, we found that the 3DL1/AP-2 interaction is diminished upon antibody engagement with the receptor, as compared to untreated cells. Thus, we have identified AP-2-mediated endocytosis as a mechanism regulating the surface levels of inhibitory KIR though their ITIM domains. Based upon our results, we propose a model in which non-engaged KIR are internalized by this mechanism, whereas engagement with MHC-I ligand would diminish AP-2 binding, thereby prolonging stable receptor surface expression and promoting inhibitory function. Furthermore, this ITIM-mediated mechanism may similarly regulate the surface expression of other inhibitory immune receptors.

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Ubiquitylation of an Internalized Killer Cell Ig-Like Receptor by Triad3A Disrupts Sustained NF-κB Signaling

Cited by 21 publications

References 42 publications

HLA-G-mediated NK cell senescence promotes vascular remodeling: implications for reproduction

HLA-G-mediated NK cell senescence promotes vascular remodeling: implications for reproduction

TNFR-Associated Factor 6 and TGF-β–Activated Kinase 1 Control Signals for a Senescence Response by an Endosomal NK Cell Receptor

The AP-2 Clathrin Adaptor Mediates Endocytosis of an Inhibitory Killer Cell Ig-like Receptor in Human NK Cells

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