FUT8介导的SEMA7A异常N-糖基化促进头颈部鳞状细胞癌的进展

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE
Zhonglong Liu, Xiaoyan Meng, Yuxin Zhang, Jingjing Sun, Xiao Tang, Zhiyuan Zhang, Liu Liu, Yue He
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引用次数: 0

摘要

SEMA7A属于Semaphorin家族,参与了肿瘤的发生和发展。异常糖基化与免疫逃逸和肿瘤生长密切相关。SEMA7A 是一种高度糖基化的蛋白质,有五个糖基化位点。SEMA7A糖基化的潜在机制及其对免疫抑制和肿瘤发生的贡献尚不清楚。在这里,我们确定了 SEMA7A 在头颈部鳞状细胞癌中的过表达和异常 N-糖基化,并阐明了岩藻糖基转移酶 FUT8 通过蛋白质与蛋白质之间的直接相互作用,催化 SEMA7A 在 N-连接寡糖(Asn 105、157、258、330 和 602)上的异常核心岩藻糖基化。SEMA7A 的糖基化雕像是其从细胞质到细胞膜的细胞内运输所必需的。细胞因子 EGF 通过增加 SEMA7A 与 FUT8 的结合亲和力来触发 SEMA7A 的 N-糖基化,而 TGF-β1 则通过诱导上皮-间质转化来促进 SEMA7A 的异常糖基化。SEMA7A 的异常 N-糖基化会导致 CD8+ T 细胞沿着衰竭状态的轨迹分化,从而形成免疫抑制性微环境,并导致抗免疫原性细胞死亡。SEMA7A的去糖基化可显著改善表皮生长因子受体靶向和基于抗PD-L1的免疫疗法的临床疗效。最后,我们还发现剪接调节因子 RBM4 是糖基化 SEMA7A 的下游效应因子,也是 PD-L1 替代剪接的关键介质。这些发现表明,靶向 FUT8-SEMA7A 轴可能是改善头颈部鳞状细胞癌患者抗肿瘤反应的一种有前途的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

FUT8-mediated aberrant N-glycosylation of SEMA7A promotes head and neck squamous cell carcinoma progression

FUT8-mediated aberrant N-glycosylation of SEMA7A promotes head and neck squamous cell carcinoma progression

SEMA7A belongs to the Semaphorin family and is involved in the oncogenesis and tumor progression. Aberrant glycosylation has been intricately linked with immune escape and tumor growth. SEMA7A is a highly glycosylated protein with five glycosylated sites. The underlying mechanisms of SEMA7A glycosylation and its contribution to immunosuppression and tumorigenesis are unclear. Here, we identify overexpression and aberrant N-glycosylation of SEMA7A in head and neck squamous cell carcinoma, and elucidate fucosyltransferase FUT8 catalyzes aberrant core fucosylation in SEMA7A at N-linked oligosaccharides (Asn 105, 157, 258, 330, and 602) via a direct protein‒protein interaction. A glycosylated statue of SEMA7A is necessary for its intra-cellular trafficking from the cytoplasm to the cytomembrane. Cytokine EGF triggers SEMA7A N-glycosylation through increasing the binding affinity of SEMA7A toward FUT8, whereas TGF-β1 promotes abnormal glycosylation of SEMA7A via induction of epithelial–mesenchymal transition. Aberrant N-glycosylation of SEMA7A leads to the differentiation of CD8+ T cells along a trajectory toward an exhausted state, thus shaping an immunosuppressive microenvironment and being resistant immunogenic cell death. Deglycosylation of SEMA7A significantly improves the clinical outcome of EGFR-targeted and anti-PD-L1-based immunotherapy. Finally, we also define RBM4, a splice regulator, as a downstream effector of glycosylated SEMA7A and a pivotal mediator of PD-L1 alternative splicing. These findings suggest that targeting FUT8-SEMA7A axis might be a promising strategy for improving antitumor responses in head and neck squamous cell carcinoma patients.

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来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
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