Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D

Stern-Ginossar, Noam; Gur, Chamutal; Biton, Moshe; Horwitz, E. P.; Elboim, Moran; Stanietsky, Noa; Mandelboim, Michal; Mandelboim, Ofer

doi:10.1038/ni.1642

Cited by 283 publications

(308 citation statements)

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“…These interactions can be quite complex as RBPs can either interact in a competitive manner or in synergism with the miRNAs that also regulate the expression of the specific transcript 48 . Interestingly, of the ten cellular miRNAs that are known to regulate MICB [18][19][20] , only one miRNA, miR-10b, was found to overlap with an RBP consensus sequence ( Supplementary Fig. 9a), and none of the herpesviruses' miRNAs 49,50 , which we characterized previously to regulate MICB, overlapped with an RBP sequence ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The fact that sequence-specific RBPs were precipitated only with the 3 0 UTR of MICB and not with MICA was surprising because MICA and MICB are commonly regulated by similar mechanisms. For example, although MICA has a much shorter 3 0 UTR than MICB (174 bp versus 1231 bp, respectively), most of the identified cellular miRNAs that target the 3 0 UTR of MICB target the MICA 3 0 UTR, as well (miR-17, -20a, -93, -106b, -372, -373 and -520d) 18 .…”

Section: Discussionmentioning

confidence: 99%

“…At the transcriptional level, the promoter regions of MICA and MICB were characterized and both include heat shock protein-binding elements 17 . At the post-transcriptional level, we have previously identified seven cellular microRNAs (miRNAs) that regulate both MICA and MICB 18 , and three additional miRNAs that regulate only MICB 19,20 . Some of these miRNAs such as the miR-17-92 cluster and miR-10b are known oncomiRs or metastamiRs, playing a crucial role in cell transformation or tumour progression.…”

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RNA-binding proteins regulate the expression of the immune activating ligand MICB

et al. 2014

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The recognition of stress-induced ligands by the activating receptor NKG2D expressed on cytotoxic lymphocytes is crucial for the prevention and containment of various diseases and is also one of the best-studied examples of how danger is sensed by the immune system. Still, however, the mechanisms leading to the expression of the NKG2D ligands are far from being completely understood. Here, we use an unbiased and systematic RNA pull-down approach combined with mass spectrometry to identify six RNA-binding proteins (RBPs) that bind and regulate the expression of MICB, one of the major stress-induced ligands of NKG2D. We further demonstrate that at least two of the identified RBPs function during genotoxic stress. Our data provide insights into stress recognition and hopefully open new therapeutic venues.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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RNA-binding proteins regulate the expression of the immune activating ligand MICB

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“…Nonetheless, some extrapolation from others models is possible. For example, MICA and MICB have been reported to be regulated by endogenous miRNAs in tumours and as a result of infection with cytomegalovirus (Stern-Ginossar et al 2008). Since miRNAs appear to play a role in regulating cellular senescence (Feliciano et al 2011;Liu et al 2012;Benhamed et al 2012) and their expression is altered in response to DNA damage (Dolezalova et al 2012;Wang and Taniguchi 2013), it is possible that changes in miRNA expression also regulate the expression of immune ligands in senescent cells.…”

Section: The Relationship Between Cell Senescence and Immune Ligand Ementioning

confidence: 99%

Cellular senescence: from growth arrest to immunogenic conversion

Burton

Faragher

2015

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Cellular senescence was first reported in human fibroblasts as a state of stable in vitro growth arrest following extended culture. Since that initial observation, a variety of other phenotypic characteristics have been shown to co-associate with irreversible cell cycle exit in senescent fibroblasts. These include (1) a proinflammatory secretory response, (2) the up-regulation of immune ligands, (3) altered responses to apoptotic stimuli and (4) promiscuous gene expression (stochastic activation of genes possibly as a result of chromatin remodeling). Many features associated with senescent fibroblasts appear to promote conversion to an immunogenic phenotype that facilitates self-elimination by the immune system. Pro-inflammatory cytokines can attract and activate immune cells, the presentation of membrane bound immune ligands allows for specific recognition and promiscuous gene expression may function to generate an array of tissue restricted proteins that could subsequently be processed into peptides for presentation via MHC molecules. However, the phenotypes of senescent cells from different tissues and species are often assumed to be broadly similar to those seen in senescent human fibroblasts, but the data show a more complex picture in which the growth arrest mechanism, tissue of origin and species can all radically modulate this basic pattern. Furthermore, wellestablished triggers of cell senescence are often associated with a DNA damage response (DDR), but this may not be a universal feature of senescent cells. As such, we discuss the role of DNA damage in regulating an immunogenic response in senescent cells, in addition to discussing less established Batypical^senescent states that may occur independent of DNA damage.

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“…Similarly, certain MIC and ULBP proteins can be upregulated by the oncogene Ras [48] or by application of histonedeacetylase inhibitors [49,50]. The expression of NKG2D-Ls was shown to be controlled by certain miRNAs [51][52][53], some of which have broad tumor-suppressive functions. Several other compounds such as dacarbazine, a cytotoxic drug used for treatment of melanoma patients [54], hydralazine and valproate, tested in cervical cancer studies [55], 5-fluorouracil used for pancreatic cancer patients or IFN-α applied in melanoma patients [56] were shown to increase NKG2D-L expression on tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Shaping of NK Cell Responses by the Tumor Microenvironment

Stojanović

Correia

Cerwenka

2012

Cancer Microenvironment

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Natural killer (NK) cells belong to the innate immune system and are potent cytolytic and cytokineproducing effector cells in response to tumor targets. NK cell based anti-tumor immunotherapy was so far mainly successful in patients with different types of leukemia. For instance, acute myeloid leukemia (AML) patients displayed a prolonged survival if transplanted with haploidentical stem cells giving rise to NK cells with a mismatch in inhibitory killer immunoglobulin receptors (KIRs) and recipients' HLA class I. Although promising results have been achieved with hematological tumors, solid tumors are in most cases poorly controlled by NK cells. Therapeutic protocols that aimed at improving NK cell responses in patients with solid malignancies succeeded in increasing NK cell numbers and functional responses of NK cells isolated from the patients' peripheral blood. However, in the majority of cases tumor progression and overall survival of patients were not significantly improved. There is increasing evidence that tumor-associated NK cells become gradually impaired during tumor progression compared to NK cells from peripheral blood and healthy tissues. Future protocols of NK cell based immunotherapy should integrate three important aspects to improve NK cell anti-tumor activity: facilitating NK cell migration to the tumor site, enhancing their infiltration into the tumor tissue and ensuring subsequent efficient activation in the tumor. This review summarizes the current knowledge of tumor-infiltrating NK cells and the influence of the tumor microenvironment on their phenotype and function.

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Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D

Cited by 283 publications

References 50 publications

RNA-binding proteins regulate the expression of the immune activating ligand MICB

RNA-binding proteins regulate the expression of the immune activating ligand MICB

Cellular senescence: from growth arrest to immunogenic conversion

Shaping of NK Cell Responses by the Tumor Microenvironment

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