Neuraminidase 1 regulates neuropathogenesis by governing the cellular state of microglia via modulation of Trem2 sialylation.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-01-14 DOI:10.1016/j.celrep.2024.115204

Leigh Ellen Fremuth, Huimin Hu, Diantha van de Vlekkert, Ida Annunziata, Jason Andrew Weesner, Alessandra d'Azzo

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引用次数: 0

Abstract

Neuraminidase 1 (NEU1) cleaves terminal sialic acids from sialoglycoproteins in endolysosomes and at the plasma membrane. As such, NEU1 regulates immune cells, primarily those of the monocytic lineage. Here, we examine how Neu1 influences microglia by modulating the sialylation of full-length Trem2 (Trem2-FL), a multifunctional receptor that regulates microglial survival, phagocytosis, and cytokine production. When Neu1 is deficient/downregulated, Trem2-FL remains sialylated, accumulates intracellularly, and is excessively cleaved into a C-terminal fragment (Trem2-CTF) and an extracellular soluble domain (sTrem2), enhancing their signaling capacities. Sialylated Trem2-FL (Sia-Trem2-FL) does not hinder Trem2-FL-DAP12-Syk complex assembly but impairs signal transduction through Syk, ultimately abolishing Trem2-dependent phagocytosis. Concurrently, Trem2-CTF-DAP12 complexes dampen NF-κB signaling, while sTrem2 propagates Akt-dependent cell survival and NFAT1-mediated production of TNF-α and CCL3. Because NEU1 and Trem2 are implicated in neurodegenerative/neuroinflammatory diseases, including Alzheimer disease and sialidosis, modulating NEU1 activity represents a therapeutic approach to broadly regulate microglia-mediated neuroinflammation.

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神经氨酸酶1通过调节Trem2唾液化调控小胶质细胞的细胞状态，从而调控神经发病机制。

神经氨酸酶1 （NEU1）在内溶酶体和质膜上从唾液糖蛋白中切割末端唾液酸。因此，NEU1调节免疫细胞，主要是那些单核细胞谱系。在这里，我们研究了Neu1如何通过调节全长Trem2 （Trem2- fl）的唾液化来影响小胶质细胞，Trem2- fl是一种调节小胶质细胞存活、吞噬和细胞因子产生的多功能受体。当Neu1缺失/下调时，Trem2-FL保持唾液化，在细胞内积累，并被过度切割成c端片段（Trem2-CTF）和细胞外可溶性结构域（sTrem2），增强其信号传导能力。唾液化的Trem2-FL （Sia-Trem2-FL）不会阻碍Trem2-FL- dap12 -Syk复合物的组装，但会损害Syk的信号转导，最终消除trem2依赖性的吞噬作用。同时，Trem2-CTF-DAP12复合物抑制NF-κB信号传导，而sTrem2促进akt依赖性细胞存活和nfat1介导的TNF-α和CCL3的产生。由于NEU1和Trem2与神经退行性/神经炎症性疾病有关，包括阿尔茨海默病和唾液中毒，因此调节NEU1活性代表了广泛调节小胶质细胞介导的神经炎症的治疗方法。

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 reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.