The Univeristy of Melbourne The Royal Melbourne Hopspital

A joint venture between The University of Melbourne and The Royal Melbourne Hospital

Publication

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


Authors:

  • Sudholz, Harrison
  • Meng, Xiangpeng
  • Park, Hae-Young
  • Shen, Zihan
  • Nikolic, Iva
  • Cursons, Joseph
  • Goddard-Borger, Ethan D.
  • Schuster, Iona S.
  • Andoniou, Christopher E.
  • Degli-Esposti, Mariapia A.
  • Scott, Nichollas E.
  • Chopin, Michael
  • Rautela, Jai
  • Scheer, Sebastian
  • Huntington, Nicholas D.

Details:

Cell Reports, Volume 44, Issue 8, 2025-08-26

Article Link: Click here

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.