Core fucosylation of IL-2RB is required for natural killer cell homeostasis

Sudholz, H; Meng, X; Park, HY; Shen, Z; Nikolic, I; Cursons, J; Goddard-Borger, ED; Schuster, IS; Andoniou, CE; Degli-Esposti, MA; Scott, NE; Chopin, M; Rautela, J; Scheer, S; Huntington, ND

Author(s): Sudholz, H; Meng, X; Park, HY; Shen, Z; Nikolic, I; Cursons, J; Goddard-Borger, ED; Schuster, IS; Andoniou, CE; Degli-Esposti, MA; Scott, NE; Chopin, M; Rautela, J; Scheer, S; Huntington, ND;
Details: Publication Year 2025-08-02,Volume 44,Issue #8,Page 116101
Journal Title: Cell Reports
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/fl)Ncr1(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.
Publisher: Cell Press
Keywords: CP: Immunology; Il-15; NK cells; core fucosylation; cytokine signaling; innate immunity; post-translational modifications; tumor immunology
Research Division(s): New Medicines and Diagnostics
PubMed ID: 40753573
Publisher's Version: https://doi.org/10.1016/j.celrep.2025.116101
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-08-08 03:15:21

Last Modified: 2025-08-08 03:15:27