Core fucosylation of IL-2RB is required for natural killer cell homeostasis
Summary: 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 fucosyl...
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| Language: | English |
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Elsevier
2025-08-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725008721 |
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| author | Harrison Sudholz Xiangpeng Meng Hae-Young Park Zihan Shen Iva Nikolic Joseph Cursons Ethan D. Goddard-Borger Iona S. Schuster Christopher E. Andoniou Mariapia A. Degli-Esposti Nichollas E. Scott Michael Chopin Jai Rautela Sebastian Scheer Nicholas D. Huntington |
| author_facet | Harrison Sudholz Xiangpeng Meng Hae-Young Park Zihan Shen Iva Nikolic Joseph Cursons Ethan D. Goddard-Borger Iona S. Schuster Christopher E. Andoniou Mariapia A. Degli-Esposti Nichollas E. Scott Michael Chopin Jai Rautela Sebastian Scheer Nicholas D. Huntington |
| author_sort | Harrison Sudholz |
| collection | DOAJ |
| description | Summary: 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 (Fut8fl/flNcr1cre/+) 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. |
| format | Article |
| id | doaj-art-82653823149b43f1a04e8b92d865f5c4 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-82653823149b43f1a04e8b92d865f5c42025-08-20T03:58:00ZengElsevierCell Reports2211-12472025-08-0144811610110.1016/j.celrep.2025.116101Core fucosylation of IL-2RB is required for natural killer cell homeostasisHarrison Sudholz0Xiangpeng Meng1Hae-Young Park2Zihan Shen3Iva Nikolic4Joseph Cursons5Ethan D. Goddard-Borger6Iona S. Schuster7Christopher E. Andoniou8Mariapia A. Degli-Esposti9Nichollas E. Scott10Michael Chopin11Jai Rautela12Sebastian Scheer13Nicholas D. Huntington14Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USADepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, AustraliaDepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, AustraliaDepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, AustraliaoNKo-Innate Pty., Ltd., 27 Norwood Cres, Moonee Ponds, VIC 3039, AustraliaoNKo-Innate Pty., Ltd., 27 Norwood Cres, Moonee Ponds, VIC 3039, AustraliaACRF, Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, AustraliaInfection and Immunity Program and Department of Microbiology Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, AustraliaInfection and Immunity Program and Department of Microbiology Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, AustraliaInfection and Immunity Program and Department of Microbiology Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, AustraliaDepartment of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC 3010, AustraliaDepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, AustraliaoNKo-Innate Pty., Ltd., 27 Norwood Cres, Moonee Ponds, VIC 3039, AustraliaDepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Department of Infection and Immunity, Luxembourg Institute of Health, 4354 Esch-sur-Alzette, LuxembourgDepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; oNKo-Innate Pty., Ltd., 27 Norwood Cres, Moonee Ponds, VIC 3039, Australia; Corresponding authorSummary: 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 (Fut8fl/flNcr1cre/+) 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.http://www.sciencedirect.com/science/article/pii/S2211124725008721CP: Immunology |
| spellingShingle | Harrison Sudholz Xiangpeng Meng Hae-Young Park Zihan Shen Iva Nikolic Joseph Cursons Ethan D. Goddard-Borger Iona S. Schuster Christopher E. Andoniou Mariapia A. Degli-Esposti Nichollas E. Scott Michael Chopin Jai Rautela Sebastian Scheer Nicholas D. Huntington Core fucosylation of IL-2RB is required for natural killer cell homeostasis Cell Reports CP: Immunology |
| title | Core fucosylation of IL-2RB is required for natural killer cell homeostasis |
| title_full | Core fucosylation of IL-2RB is required for natural killer cell homeostasis |
| title_fullStr | Core fucosylation of IL-2RB is required for natural killer cell homeostasis |
| title_full_unstemmed | Core fucosylation of IL-2RB is required for natural killer cell homeostasis |
| title_short | Core fucosylation of IL-2RB is required for natural killer cell homeostasis |
| title_sort | core fucosylation of il 2rb is required for natural killer cell homeostasis |
| topic | CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725008721 |
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