O-GlcNAcylation of UGDH regulates its activity and remodels the extracellular matrix to facilitate tumor growth.

IF 15.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Bingyi Lin, Junjie Zhou, Didi Geng, Siyuan Chai, Xuanming Zhang, Zengle Zhang, Jiating Hu, Qin Tang, Xiaoming Chen, Wen Yi, Liming Wu
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引用次数: 0

Abstract

The tumor microenvironment is an immunosuppressive niche that contributes to tumor growth by downregulating immune cell functions or restraining immune cell infiltration. The underlying mechanisms are not still poorly understood. Here, we demonstrate that O-linked N-acetylglucosamine (O-GlcNAcylation), a prevalent form of protein glycosylation, contributes to establishing the immunosuppressive niche through regulating the metabolic and non-metabolic functions of uridine diphosphate glucose dehydrogenase (UGDH). Tumor cells carrying O-GlcNAcylation-deficient UGDH showed reduced xenograft tumor growth and improved survival in mice. Cytometry by time-of-flight (CyTOF) analysis suggests UGDH O-GlcNAcylation negatively correlates with cytotoxic CD8+ T cell infiltration. O-GlcNAcylation on serine 350 of UGDH is located within the UDP-binding domain, and the subsequent extensive all-atom molecular dynamics simulations reveal that O-GlcNAcylation reinforces hydrogen-bonding interaction and enzymatic activity of UGDH, leading to enhanced hyaluronic acid (HA) synthesis in the extracellular matrix. Moreover, O-GlcNAcylation of UGDH reduces CD8+ T cell infiltration by decreasing the chemokine CXCL10 expression. Specifically, O-GlcNAcylation enhances UGDH interaction with KPNA2 to compete with STAT1, and suppresses translocation of STAT1 into the nucleus, thereby transcriptionally downregulating CXCL10 expression. Thus, our study identifies UGDH O-GlcNAcylation as a key regulator of tumor immunity and further suggests a potential strategy for enhancing immunotherapy.

UGDH的o - glcn酰化调节其活性,重塑细胞外基质,促进肿瘤生长。
肿瘤微环境是一个免疫抑制生态位,通过下调免疫细胞功能或抑制免疫细胞浸润来促进肿瘤生长。人们对其潜在的机制还不是很了解。在这里,我们证明了O-linked N-acetylglucosamine (o - glcnac酰化),一种普遍的蛋白质糖基化形式,通过调节尿苷二磷酸葡萄糖脱氢酶(UGDH)的代谢和非代谢功能,有助于建立免疫抑制生态位。携带o - glcn酰化缺陷UGDH的肿瘤细胞在小鼠中显示出异种移植物肿瘤生长减少和生存率提高。细胞飞行时间(CyTOF)分析显示,UGDH o - glcn酰化与细胞毒性CD8+ T细胞浸润呈负相关。UGDH丝氨酸350上的o - glcn酰化位于udp结合区域内,随后广泛的全原子分子动力学模拟表明,o - glcn酰化增强了UGDH的氢键相互作用和酶活性,从而增强了细胞外基质中透明质酸(HA)的合成。此外,UGDH的o - glcn酰化通过降低趋化因子CXCL10的表达来减少CD8+ T细胞的浸润。具体来说,o - glcn酰化增强了UGDH与KPNA2的相互作用,从而与STAT1竞争,抑制STAT1转位进入细胞核,从而转录下调CXCL10的表达。因此,我们的研究确定了UGDH o - glcn酰化是肿瘤免疫的关键调节因子,并进一步提出了增强免疫治疗的潜在策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Death and Differentiation
Cell Death and Differentiation 生物-生化与分子生物学
CiteScore
24.70
自引率
1.60%
发文量
181
审稿时长
3 months
期刊介绍: Mission, vision and values of Cell Death & Differentiation: To devote itself to scientific excellence in the field of cell biology, molecular biology, and biochemistry of cell death and disease. To provide a unified forum for scientists and clinical researchers It is committed to the rapid publication of high quality original papers relating to these subjects, together with topical, usually solicited, reviews, meeting reports, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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