<em>Core fucosylation of IL-2RB is required for natural killer cell homeostasis</em> — ASN Events
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Core fucosylation of IL-2RB is required for natural killer cell homeostasis (#188)

Harrison Sudholz 1 , Hae-Young Park 2 , Xiangpeng Meng 2 , Zihan Shen 2 , Iva Nikolic 3 , Joseph Cursons 3 , Ethan D Goddard-Borger 4 , Iona S Schuster 5 , Christopher E Andoniou 5 , Mariapia A Degli-Esposti 5 , Nichollas E Scott 6 , Michael Chopin 2 , Jai Rautela 3 , Sebastian Scheer 7 , Nicholas D Huntington 2
  1. University of California, Berkeley, Berkeley, California, United States
  2. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic, Australia
  3. Onko-Innate Pty Ltd, Melbourne, Vic, Australia
  4. Chemical and Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia
  5. Department of Microbiology, Monash University, Clayton, Vic, Australia
  6. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, Parkville, Vic, Australia
  7. Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg

Natural Killer (NK) cell homeostasis and effector function require context-dependent signalling via numerous receptors including the IL-15 receptor. Post-translational modifications can regulate receptor signalling, 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 signalling and NK cell biology, mice lacking Fut8 in NK cells (Fut8fl/flNcr1cre/+) were generated. Loss of core fucose in NK cells resulted in severe NK cell lymphopenia associated with a reduction in IL-15 receptor beta (IL2RB/CD122) expression and impaired in vivo homeostatic proliferation. Interestingly, ablation of intrinsic apoptosis could not reverse Fut8-null NK cell lymphopenia indicating that normal IL-15R expression and signalling is essential for filling the NK cell niche via homeostatic proliferation. These data suggest that steady-state NK cell proliferation is highly sensitive to alterations in CD122 expression levels. Loss of core fucose impaired NK cell cytotoxicity, tumour and early viral control. Taken together, we have identified FUT8 as a key modulator of NK cell biology by regulating IL-15R expression and signalling.