@article{9139c86cf8384b39ba16b4ad269afaf0,
title = "Core fucosylation of IL-2RB is required for natural killer cell homeostasis",
abstract = "Natural killer (NK) cell homeostasis and effector functions require context-dependent signaling via numerous receptors, including the interleukin-15 receptor (IL-15R). Post-translational modifications can regulate receptor signaling, impacting receptor turnover and trafficking. Core fucosylation is one such modification known to impact receptor expression and is uniquely mediated by fucosyltransferase 8 (FUT8). We identified FUT8 as an essential gene required for IL-15R responsiveness in a human NK cell genome-wide CRISPR screen. To further validate core fucosylation in IL-15R signaling and NK cell biology, mice lacking Fut8 in NK cells (Fut8 fl/flNcr1 cre/+) were generated. The loss of core fucose in murine NK cells resulted in severe NK cell lymphopenia, with a reduction in IL-15Rβ (IL-2RB/CD122) expression, impairing in vivo homeostatic proliferation. The loss of FUT8 also decreased NK cell cytotoxicity, tumor immunity, and early viral immunity. Taking these results together, we have identified FUT8 as a key modulator of NK cell biology by regulating their development, IL-15R expression, and signaling. ",
keywords = "Animals, Fucose/metabolism, Fucosyltransferases/metabolism, Homeostasis, Humans, Interleukin-2 Receptor beta Subunit/metabolism, Killer Cells, Natural/metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Signal Transduction",
author = "Harrison Sudholz and Xiangpeng Meng and Hae-Young Park and Zihan Shen and Iva Nikolic and Joseph Cursons and Goddard-Borger, \{Ethan D\} and Schuster, \{Iona S\} and Andoniou, \{Christopher E\} and Degli-Esposti, \{Mariapia A\} and Scott, \{Nichollas E\} and Michael Chopin and Jai Rautela and Sebastian Scheer and Huntington, \{Nicholas D\}",
note = "Funding: This work is supported by project grants from the National Health and Medical Research Council (NHMRC) of Australia (GNT1124784, GNT1066770, GNT1057852, GNT1124907, GNT1057812, GNT1049407, GNT1027472, and GNT1184615 to N.D.H. and GNT2004397 to M.A.D.-E. and C.E.A.) and an NHMRC Investigator Fellowship (GNT1195296 to N.D.H. and GNT2026377 to M.A.D.-E.). N.D.H. is a recipient of a Melanoma Research Grant from the Harry J. Lloyd Charitable Trust, a Melanoma Research Alliance Young Investigator Award, an Ian Potter Foundation equipment grant, the Na- tional Foundation for Medical Research and Innovation (NFMRI) John Dixon Hughes Medal, and a CLIP grant from the Cancer Research Institute. M.A. D.-E. received support from the Australian Research Council grant DP230102854. The functional genomics, NK cell screening platform, and computational biology were funded by oNKo-Innate Pty., Ltd. H.S. is a recip- ient of an Australian Government Research Training Program (RTP) Scholar- ship, a Cancer Research Institute Irvington Postdoctoral Fellowship, and a Monash University Postgraduate Publications Award. Copyright {\textcopyright} 2025 The Author(s). Published by Elsevier Inc. All rights reserved.",
year = "2025",
month = aug,
day = "26",
doi = "10.1016/j.celrep.2025.116101",
language = "English",
volume = "44",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "8",
}