IL-2RB的核心岩藻糖基化是自然杀伤细胞稳态所必需的。

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

作者信息

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

机构信息

Department 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, USA.

Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.

出版信息

Cell Rep. 2025 Aug 26;44(8):116101. doi: 10.1016/j.celrep.2025.116101. Epub 2025 Aug 2.

DOI:10.1016/j.celrep.2025.116101

PMID:40753573

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 (Fut8Ncr1) 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.

摘要

自然杀伤（NK）细胞的稳态和效应功能需要通过众多受体进行依赖于上下文的信号传导，包括白细胞介素-15受体（IL-15R）。翻译后修饰可以调节受体信号传导，影响受体的周转和运输。核心岩藻糖基化就是这样一种已知会影响受体表达的修饰，并且由岩藻糖基转移酶8（FUT8）独特地介导。在一项人类NK细胞全基因组CRISPR筛选中，我们将FUT8鉴定为IL-15R反应性所需的必需基因。为了进一步验证IL-15R信号传导和NK细胞生物学中的核心岩藻糖基化，我们构建了NK细胞中缺乏Fut8的小鼠（Fut8Ncr1）。小鼠NK细胞中核心岩藻糖的缺失导致严重的NK细胞淋巴细胞减少，IL-15Rβ（IL-2RB/CD122）表达降低，损害体内稳态增殖。FUT8的缺失还降低了NK细胞的细胞毒性、肿瘤免疫和早期病毒免疫。综合这些结果，我们通过调节NK细胞的发育、IL-15R表达和信号传导，将FUT8鉴定为NK细胞生物学的关键调节因子。