PXD063595-1

PXD063595 is an original dataset announced via ProteomeXchange.

Title	UBE2F inhibits Natural Killer cell tumor immunity by activating the ARIH2-CRL5 complex to degrade interleukin 15 receptors
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.
HostingRepository	PRIDE
AnnounceDate	2025-07-11
AnnouncementXML	Submission_2025-07-11_08:52:22.547.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joseph Cursons
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2025-05-04 21:53:38	ID requested
⏵ 1	2025-07-11 08:52:23	announced

Nikolic I, Cursons J, Shields B, Chappaz S, Sudholz H, Meng X, Constantinescu P, Vijayakumaran R, D'Angelo M, Foroutan M, Ladd D, Veldman M, Glab J, Procter T, Park HY, Contet J, Deuss F, Wong K, Sun Y, Berry R, Rautela J, Huntington ND, Enhancing anti-tumor immunity of natural killer cells through targeting IL-15R signaling. Cancer Cell, ():(2025) [pubmed]

10.1016/j.ccell.2025.05.011;

submitter keyword: Human, natural killer cells, UBE2F knockout

Nicholas D Huntington
contact affiliation	Chief Scientific Officer oNKo-innate Pty Ltd Laboratory Head, Huntington Laboratory Monash Biomedicine Discovery Institute Monash University Victoria Australia
contact email	nick@onko-innate.com
lab head
Joseph Cursons
contact affiliation	oNKo-innate Pty Ltd
contact email	joe@onko-innate.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD063595
     1. Label: PRIDE project
     2. Name: UBE2F inhibits Natural Killer cell tumor immunity by activating the ARIH2-CRL5 complex to degrade interleukin 15 receptors