Brief Residence at the Plasma Membrane of the MHC Class I-Related Chain B Is Due to Clathrin-Mediated Cholesterol-Dependent Endocytosis and Shedding

Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
The Journal of Immunology (Impact Factor: 4.92). 05/2009; 182(8):4800-8. DOI: 10.4049/jimmunol.0800713
Source: PubMed


Recognition of MHC class I-related chain (MIC) molecules on the surface of target cells by the activating receptor NKG2D leads to their lysis by immune effector cells. Up-regulation of NKG2D ligands is broadly related to stress, although the detailed molecular mechanisms that control the presence of these molecules at the plasma membrane are unclear. To investigate the posttranslational mechanisms that control surface expression of the human NKG2D ligand MICB, we studied the subcellular localization and trafficking of this molecule. We found that in several cellular systems, the expression of MICB molecules on the cell surface is accompanied by an intracellular accumulation of the molecule in the trans-Golgi network and late endosome-related compartments. Surprisingly, MICB has a much shorter half-life at the plasma membrane than MHC molecules and this depends on both recycling to internal compartments and shedding to the extracellular medium. Internalization of MICB depends partially on clathrin, but importantly, the lipid environment of the membrane also plays a crucial role in this process. We suggest that the brief residence of MICB at the plasma membrane modulates, at least in part, the function of this molecule in the immune system.

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Available from: Hugh T Reyburn, Oct 04, 2015
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    • "Another suggestion was that the GPI-linked ligands are preferably expressed on exosomes since GPI-anchored proteins are preferably enriched in DRM and thus they will be internalized to early and late endosomes and eventually end up on exosomes that are released in the intercellular space. In line with this suggestion it was shown that the GPI-linked ULBP1-3 were recruited to DRM regions [61] while only a low proportion of the transmembranally attached MICA/B molecules were present in DRM [62]. Although this observation was experimentally substantiated it is not a general rule for all or for a particular NKG2D ligand(s). "
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    ABSTRACT: Human cancers constitutively produce and release endosome-derived nanometer-sized vesicles called exosomes that carry biologically active proteins, messenger and micro RNAs and serve as vehicles of intercellular communication. The tumor exosomes are present in the blood, urine and various malignant effusions such as peritoneal and pleural fluid of cancer patients and can modulate immune cells and responses thus deranging the immune system of cancer patients and giving advantage to the cancer to establish and spread itself. Here, the role of exosomes in the NKG2D receptor-ligand system's interactions is discussed. The activating NK cell receptor NKG2D and its multiple ligands, the MHC class I-related chain (MIC) A/B and the retinoic acid transcript-1/UL-16 binding proteins (RAET1/ULBP) 1-6 comprise a powerful stress-inducible danger detector system that targets infected, inflamed and malignantly transformed cells and plays a decisive role in anti-tumor immune surveillance. Mounting evidence reveals that the MIC- and RAET1/ULBP ligand family members are enriched in the endosomal compartment of various tumor cells and expressed and released into the intercellular space and bodily fluids on exosomes thus preserving their entire molecule, three-dimensional protein structure and biologic activity. The NKG2D ligand-expressing exosomes serve as decoys with a powerful ability to down regulate the cognate receptor and impair the cytotoxic function of NK-, NKT-, gamma/delta- and cytotoxic T cells. This review summarizes recent findings concerning the role of NKG2D receptor-ligand system in cancer with emphasis on regulation of NKG2D ligand expression and the immunosuppressive role of exosomally expressed NKG2D ligands.
    Seminars in Cancer Biology 10/2014; 28(1). DOI:10.1016/j.semcancer.2014.02.010 · 9.33 Impact Factor
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    • "Another possibly relevant difference between GPI-anchored and TM proteins is that GPI-anchored proteins usually associate with detergent resistant membranes (DRMs), which are regions of the membrane enriched in sphingolipids and cholesterol. Indeed, the majority of ULBP1–3 proteins are recruited to these regions of the membrane (Fernandez-Messina et al., 2010) while only a low proportion of MICA/B appears in DRMs (Aguera-Gonzalez et al., 2009). However , this statement does not seem to be a general rule for MICs, since a high proportion of MICA*008 molecules are also recruited to DRMs (Ashiru et al., 2010). "
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    ABSTRACT: Immune recognition mediated by the activating receptor NKG2D plays an important role for the elimination of stressed cells, including tumors and virus-infected cells. On the other hand, the ligands for NKG2D can also be shed into the sera of cancer patients where they weaken the immune response by downmodulating the receptor on effector cells, mainly NK and T cells. Although both families of NKG2D-ligands, major histocompatibility complex class I-related chain (MIC) A/B and UL16 binding proteins (ULBPs), are related to MHC molecules and their expression is increased after stress, many differences are observed in terms of their biochemical properties and cell trafficking. In this paper, we summarize the variety of NKG2D-ligands and propose that selection pressure has driven evolution of diversity in their trafficking and shedding, but not receptor binding affinity. However, it is also possible to identify functional properties common to individual ULBP molecules and MICA/B alleles, but not generally conserved within the MIC or ULBP families. These characteristics likely represent examples of convergent evolution for efficient immune recognition, but are also attractive targets for pathogen immune evasion strategies. Categorization of NKG2D-ligands according to their biological features, rather than their genetic family, may help to achieve a better understanding of NKG2D-ligand association with disease.
    Frontiers in Immunology 09/2012; 3:299. DOI:10.3389/fimmu.2012.00299
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    • "Therefore, an issue of vital importance will be to address if both soluble MICA and MICB share the same biological function in patients with HPV-associated tumors and to determine whether MICB, which was found in a higher concentration than MICA in the supernatants of cervical cancer cell lines, could promote NKG2D downmodulation in NK cells of cervical cancer patients. It will be also interesting to investigate if MICA and MICB show different mechanisms of posttranslational control; for instance, Agüera-González et al., showed recently that MICB has a short time of residence at the plasma membrane and demonstrated that MICB shedding was one of the mechanisms that contributes to the rapid loss of ligand from the cell surface [53]. Thus, if high levels of soluble MICB are present in the serum of cervical cancer patients, and this contributes to tumor immune escape, targeting of this molecule could be a promising alternative to improve tumor immunosurveillance in these patients. "
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    ABSTRACT: Natural killer (NK) cells are an important resource of the innate immune system directly involved in the spontaneous recognition and lysis of virus-infected and tumor cells. An exquisite balance of inhibitory and activating receptors tightly controls the NK cell activity. At present, one of the best-characterized activating receptors is NKG2D, which promotes the NK-mediated lysis of target cells by binding to a family of cell surface ligands encoded by the MHC class I chain-related (MIC) genes, among others. The goal of this study was to describe the expression pattern of MICA and MICB at the molecular and cellular levels in human cervical cancer cell lines infected or not with human papillomavirus, as well as in a non-tumorigenic keratinocyte cell line. Here we show that MICA and MICB exhibit differential expression patterns among HPV-infected (SiHa and HeLa) and non-infected cell lines (C33-A, a tumor cell line, and HaCaT, an immortalized keratinocyte cell line). Cell surface expression of MICA was higher than cell surface expression of MICB in the HPV-positive cell lines; in contrast, HPV-negative cells expressed lower levels of MICA. Interestingly, the MICA levels observed in C33-A cells were overcome by significantly higher MICB expression. Also, all cell lines released higher amounts of soluble MICB than of soluble MICA into the cell culture supernatant, although this was most pronounced in C33-A cells. Additionally, Real-Time PCR analysis demonstrated that MICA was strongly upregulated after genotoxic stress. This study provides evidence that even when MICA and MICB share a high degree of homology at both genomic and protein levels, differential regulation of their expression and cell surface appearance might be occurring in cervical cancer-derived cells.
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