Dataset Information

UBE2F inhibits Natural Killer cell tumor immunity by activating the ARIH2-CRL5 complex to degrade interleukin 15 receptors

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE296451 | GEO | 2025/05/13

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Gene-expression profiles of hepatic stellate cells isolated from IL15R-alpha knockout mouse IL-15 and its high affinity receptor IL-15Rα are widely expressed in immune cells including dendritic cells and macrophages and non-immune cells such as hepatocytes, oval cells and hepatic stellate cells (HSC). IL-15 signaling has important functions in natural killers (NK), natural killers T (NKT) and cytotoxic T (CD8+T) cell homeostasis and also in liver regeneration. We hypothesized that IL-15 may have a protective role during liver fibrosis progression due to its role in NK cell homeostasis. We compared fibrosis progression in IL-15Rα knockout mice (IL-15RαKO) to wild type mice using two mechanistically distinct models, chronic carbon tetrachloride (CCl4) exposure and bile duct ligation (BDL). Enhanced fibrosis progression was observed in IL-15RαKO mice in both models. Furthermore, using congenic bone marrow transplantation (BMT), we demonstrated an unexpected role for IL-15 signaling in hepatic resident cells for the maintenance of liver NK and CD8+T cell populations. Using this approach, transplanting IL-15RKO hematopoietic cells results in NK defect that surprisingly is not reflected in a change of fibrosis progression. However, chimeric mice with defect of IL-15R on liver resident cells have similar NK defects and significant more fibrosis after CCL4 liver injury. This supports a direct protective, anti-fibrogenic role for IL-15R on one of the radioresistant liver cell populations (hepatocytes, HSC and sessile Kupffer cells). Microarray analysis of IL15RKO HSC suggests up-regulation of collagen transcripts and down-regulation of pathways involved in cell proliferation/survival. Finally, activated HSCs isolated from IL-15RKO mice show increased collagen secretion and as predicted, no changes in the growth curves. In summary, IL-15Rα signaling has an anti-fibrotic effect through both BM-derived and hepatic resident cells. These findings establish a rationale to explore IL-15 signaling in HSC as a potential therapeutic target in liver fibrogenesis.

Dataset Information

UBE2F inhibits Natural Killer cell tumor immunity by activating the ARIH2-CRL5 complex to degrade interleukin 15 receptors

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets