UBE2F inhibits Natural Killer cell tumor immunity by activating the ARIH2-CRL5 complex to degrade interleukin 15 receptors
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ABSTRACT:
PROVIDER: PRJNA1259407 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33446736_1.fastq.gz | Fastqsanger.gz | |||
| SRR33446736_2.fastq.gz | Fastqsanger.gz | |||
| SRR33446737_1.fastq.gz | Fastqsanger.gz | |||
| SRR33446737_2.fastq.gz | Fastqsanger.gz | |||
| SRR33446738_1.fastq.gz | Fastqsanger.gz |
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Project description:Interleukin-15 receptor (IL-15R) agonists induce anti-tumor immunity in pre-clinical models, however, dose-limiting toxicity has hampered their clinical development. An alternative is to target pathways downstream of the IL-15R to access different therapeutic profiles. We performed genome-wide CRISPR screens to reveal the complete IL15R signaling mechanism in NK cells and discovered ubiquitin-dependent IL15R degradation as the dominant mechanism restraining IL-15R signaling. Top hits included the NEDD8 E2conjugating enzyme UBE2F & ubiquitin E3-ligase ARIH2, along with Cullin-5 RING E3 Ligase (CRL5) members. UBE2F was required for CUL5 neddylation/activation whereas ARIH2 contributed to CRL5-mediated IL-15RB degradation. Ablation of ARIH2 or UBE2F enhanced IL-15RB surface expression/signaling & proinflammatory cytokine production, and augmented natural & CAR-mediated cytotoxicity. In mice lacking Arih2, Rnf7 or Ube2f, IL-15R hyperresponsive NK cells resulted in superior in vivo anti-tumor immunity against primary and disseminated metastatic tumors. Thus, we have identified the enzymes UBE2F and ARIH2 as tractable immunotherapy drug targets.
2025-07-11 | PXD063595 | Pride
Project description:Interleukin-15 receptor (IL-15R) agonists induce anti-tumor immunity in pre-clinical models, however, dose-limiting toxicity has hampered their clinical development. An alternative is to target pathways downstream of the IL-15R to access different therapeutic profiles. We performed genome-wide CRISPR screens to reveal the complete IL15R signaling mechanism in NK cells and discovered ubiquitin-dependent IL15R degradation as the dominant mechanism restraining IL-15R signaling. Top hits included the NEDD8 E2conjugating enzyme UBE2F & ubiquitin E3-ligase ARIH2, along with Cullin-5 RING E3 Ligase (CRL5) members. UBE2F was required for CUL5 neddylation/activation whereas ARIH2 contributed to CRL5-mediated IL-15RB degradation. Ablation of ARIH2 or UBE2F enhanced IL-15RB surface expression/signaling & proinflammatory cytokine production, and augmented natural & CAR-mediated cytotoxicity. In mice lacking Arih2, Rnf7 or Ube2f, IL-15R hyperresponsive NK cells resulted in superior in vivo anti-tumor immunity against primary and disseminated metastatic tumors. Thus, we have identified the enzymes UBE2F and ARIH2 as tractable immunotherapy drug targets.
2025-05-13 | GSE296451 | GEO
Project description:We report here the design of new antibody-based natural killer cell engager therapeutics (ANKET), single tetraspecific molecules engaging the NK cell activating receptors NKp46 and CD16, the β chain of the interleukin-2 receptor (IL-2R) and a tumor-associated antigen (TAA).
2022-10-05 | GSE214378 | GEO
Project description:The CD8+ T cell compartment of human cytomegalovirus (CMV) seropositive individuals characteristically contains a high proportion of cells that expresses Natural Killer Cell Receptors (NKR) which may contribute to the surveillance of virus-infected cells. To test if this enhanced expression is a direct and immediate result of CMV infection we used DNA microarrays to analyse putative changes in RNA-expression level of 39 NKRs in CMV-specific CD8+ T cells of renal transplant recipients experiencing primary CMV infection. Already in the acute phase of infection 29 NKRs were induced of which 19 remained high 1 year after cessation of viral replication. Activating and inhibitory NKRs were induced to a similar extent. Detailed longitudinal flowcytometric analyses confirmed NKR changes at the protein level. Strikingly, a strong induction of CD94 on CD3+ T cells was observed with surface expression of activating CD94dimNKG2C dimers appearing before inhibitory CD94brightNKG2A ones. After the acute phase of infection, the balance between inhibitory and activating receptors did not change. Thus, CMV infection induces a rapid and lasting change in the expression of NK receptors on human CD8+ T cells. Keywords: primary cytomegalovirus infection, human, CD8+ T cells, NKR, latent infection, chronic infection CMV-specific CD8+ T cells were isolated at three different stages (peak, 1 year p.i, latent) from three CMV seropositive individuals. Total RNA for each stage was pooled and compared with pooled RNA of naive CD8+ T-cells from healthy controls. For quality control naive CD8+ T-cells were compared with naive CD8+ T-cells. The experiment was performed in dye-swap.
2008-08-28 | E-GEOD-12589 | biostudies-arrayexpress
Project description:The CD8+ T cell compartment of human cytomegalovirus (CMV) seropositive individuals characteristically contains a high proportion of cells that expresses Natural Killer Cell Receptors (NKR) which may contribute to the surveillance of virus-infected cells. To test if this enhanced expression is a direct and immediate result of CMV infection we used DNA microarrays to analyse putative changes in RNA-expression level of 39 NKRs in CMV-specific CD8+ T cells of renal transplant recipients experiencing primary CMV infection. Already in the acute phase of infection 29 NKRs were induced of which 19 remained high 1 year after cessation of viral replication. Activating and inhibitory NKRs were induced to a similar extent. Detailed longitudinal flowcytometric analyses confirmed NKR changes at the protein level. Strikingly, a strong induction of CD94 on CD3+ T cells was observed with surface expression of activating CD94dimNKG2C dimers appearing before inhibitory CD94brightNKG2A ones. After the acute phase of infection, the balance between inhibitory and activating receptors did not change. Thus, CMV infection induces a rapid and lasting change in the expression of NK receptors on human CD8+ T cells. Keywords: primary cytomegalovirus infection, human, CD8+ T cells, NKR, latent infection, chronic infection
2008-08-28 | GSE12589 | GEO
Project description:Natural Killer cells (NK), a major constituent of innate immune system, have the ability to kill the transformed and infected cells without prior sensitization; can be put to immunotherapeutic use against various malignancies. NK cells discriminate between normal cells and transformed cells via a balance of inhibitory and activating signals induced by interactions between NK cell receptors and target cell ligands. Present study investigates whether expansion of NK cells could augment their anti-myeloma (MM) activity. For NK cell expansion, peripheral blood mononuclear cells from healthy donors and myeloma patients were co-cultured with irradiated K562 cells transfected with 4-1BBL and membrane-bound IL15 (K562-mb15-41BBL). A genome-wide profiling approach was performed to identify gene expression signature in expanded NK (ENK) cells and non-expanded NK cells isolated from healthy donors and myeloma patients. A specific set of genes involved in proliferation, migration, adhesion, cytotoxicity, and activation were up regulated post expansion, also confirmed by flow cytometry. Exp-NK cells killed both allogeneic and autologous primary MM cells more avidly than non-exp-NK cells in vitro. Multiple receptors, particularly NKG2D, natural cytotoxicity receptors, and DNAM-1 contributed to target lysis, via a perforin mediated mechanism. In summary, vigorous expansion and high anti-MM activity both in vitro and in vivo provide the rationale for testing exp-NK cells in a clinical trial for high risk MM. Differential gene expression profile in expanded natural killer (ENK) cells and non-expanded natural killer (NK) cells from healthy donors and myeloma patients Eight healthy donor and eight myeloma patients were used in the study. Non-expanded natural killer (NK) cells were isolated from PBMCs of healthy donors and myeloma patients. Expanded natural killer (ENK) cells were generated from same set of samples as mentioned in expansion protocol. All ENK and NK cells were used for gene expression profiling.
2011-03-08 | E-GEOD-27838 | biostudies-arrayexpress
Project description:Sequential Exposure to Interleukin-21 and Interleukin-15 During Human Natural Killer Cell Expansion Optimizes Yield and Function
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Project description:An allorecognition system depending on interactions between uterine Natural Killer (uNK) cells and placental extravillous trophoblast (EVT) during early pregnancy influences reproductive outcomes in humans. Our previous immunogenetic studies show that particular combinations of maternal Killer Immunoglobulin-like Receptors (KIR) in uNK cells with fetal HLA-C variants on EVT are associated with disorders of pregnancy, especially pre-eclampsia. To identify responses stimulated in uNK cells specifically when activating KIR (KIR2DS1) binds to C2+HLA-C, a combination protective against pre-eclampsia, we modelled KIR-HLA interactions by co-culturing uNK cells with the 721.221 HLA-null cell line transfected to express either C1+ or C2+HLA-C molecules, followed by transcriptome profiling by RNA sequencing. We detect the secretion of key cytokines by uNK cells under the protective combination between KIR2DS1 and C2+HLA-C.
2024-01-10 | E-MTAB-13379 | biostudies-arrayexpress
Project description:The release of soluble ligands of activating Natural Killer (NK) cell receptors may represent a regulatory mechanism of NK cell function both in physiologic and in pathologic conditions. Here, we identified the extracellular matrix protein Nidogen-1 (NID1) as a ligand of NKp44, an important activating receptor expressed by activated NK cells. When released as soluble molecule, NID1 can regulate NK cell function by modulating NKp44-induced IFN-γ production or cytotoxicity. We also show that NID1 may be present at the cell surface. In this form or when bound to a solid support (bNID1), NID1 failed to induce NK cell cytotoxicity or cytokine release. However, analysis by mass spectrometry revealed that exposure to bNID1 can induce relevant changes in the proteomic profiles suggesting an effect on different, biological processes of human NK cells.
2018-10-22 | PXD008252 | Pride
Project description:Natural killer (NK) cells may play an important role in the pathogenesis of SLE. Interleukin(IL)-15, an NK-enhancing cytokine, is over-expressed in SLE patients. In the present study, we examined the effect of IL-15 on NK cytotoxicity of SLE patients, and the expression of various activating and inhibitory NK receptors on NK cells from SLE patients in relation to disease activity. We also sought to determine how IL-15 would affect the NK receptor expression on NK cells from SLE patients. PBMCs were collected from 88 SLE patients with inactive disease activity (SLEDAI score<6) and active disease activity (SLEDAI score≥6), 26 age-matched healthy adults were used as controls. PBMC were incubated in the presence or absence of IL-15 (10ng/ml) for eighteen hours. CD3-CD56+ lymphoctes were gated using flow cytometry and further divided into CD56dim and CD56bright subsets according to the MFI of CD56. We observed that 1. Serum IL-15 was elevated in SLE patients, and higher in active disease than in inactive disease; 2. NK cytotoxicity of SLE patients was deficient compared to controls and showed an impaired response to IL-15 compared to controls; 3.CD69, CD94, NKG2A, NKp30, and CD158b on NK cells from SLE patients were higher than controls, and could be further enhanced by IL-15; 4. NKp46 expression from SLE patients was higher than controls, but down-regulated by IL-15; 5.Deficient NKG2D and NKAT-2 expression were found on NK cells from SLE patients, which were enhanced by IL-15; 6. A unique NKp46- subset and CD158b+ subsets were observed in NK cells from SLE patients but not controls. 7. Unlike controls, CD158k on NK cells from SLE patients failed to respond to IL-15. Taken together, we demonstrated the aberrant NCR and iNKR expression on NK cells and their distinct response to IL-15 in SLE patients. As IL-15 predominantly aggravates the aberrant NKR expression found in SLE, IL-15 antagonist may have therapeutic benefits in SLE patients.
| S-EPMC5638402 | biostudies-literature