Macrophage USP14 suppresses Wnt/β-catenin signaling via NLK deubiquitination to enhance immune response

IF 3.6 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine Pub Date : 2026-02-01 Epub Date: 2025-12-06 DOI:10.1016/j.cyto.2025.157079

Mingming Zhao , Junjie Shi , Xinqi Wei , Wenze Tian , Yuee Chen

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Abstract

Macrophages are key immune cells that regulate the body's immune response by promoting the release of inflammatory cytokines upon recognition of both endogenous and exogenous pathogens. USP14, a critical deubiquitinase, plays a vital role in various cellular processes, especially in modulating immune responses. This study aims to investigate the role of USP14 in regulating macrophage immune responses. USP14 overexpression and knockdown were performed in RAW264.7 cells and mouse bone marrow macrophages via plasmid transfection and lentiviral infection, respectively. Our research demonstrates that USP14 overexpression amplified the LPS-induced inflammatory response and promoted macrophage migration, whereas USP14 knockdown produced the opposite effects. USP14 interacts with NLK, thereby attenuating Wnt/β-catenin signaling and concurrently activating the NF-κB pathway in macrophages. USP14 facilitates the deubiquitination of NLK, thereby stabilizing its activity. Moreover, the USP14 inhibitor IU1 reduces the LPS-induced inflammatory response in macrophages. Mechanistically, macrophage USP14 facilitates the deubiquitination of NLK, thereby maintaining its activity, inhibiting the Wnt/β-catenin pathway, activating the NF-κB pathway, and enhancing the cellular immune response.

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巨噬细胞USP14通过NLK去泛素化抑制Wnt/β-catenin信号，增强免疫应答

巨噬细胞是调节机体免疫反应的关键免疫细胞，在识别内源性和外源性病原体时，通过促进炎症因子的释放来调节机体的免疫反应。USP14是一种关键的去泛素酶，在各种细胞过程中起着至关重要的作用，特别是在调节免疫反应中。本研究旨在探讨USP14在调节巨噬细胞免疫应答中的作用。通过质粒转染和慢病毒感染分别在RAW264.7细胞和小鼠骨髓巨噬细胞中过表达和敲低USP14。我们的研究表明，USP14过表达放大了lps诱导的炎症反应，促进了巨噬细胞的迁移，而USP14敲低则产生相反的效果。USP14与NLK相互作用，从而减弱巨噬细胞中Wnt/β-catenin信号通路，同时激活NF-κB通路。USP14促进NLK的去泛素化，从而稳定其活性。此外，USP14抑制剂IU1可降低lps诱导的巨噬细胞炎症反应。机制上，巨噬细胞USP14促进NLK去泛素化，从而维持其活性，抑制Wnt/β-catenin通路，激活NF-κB通路，增强细胞免疫应答。

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来源期刊

Cytokine 医学-免疫学

CiteScore

7.60

自引率

2.60%

发文量

262

审稿时长

48 days

期刊介绍： The journal Cytokine has an open access mirror journal Cytokine: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review. * Devoted exclusively to the study of the molecular biology, genetics, biochemistry, immunology, genome-wide association studies, pathobiology, diagnostic and clinical applications of all known interleukins, hematopoietic factors, growth factors, cytotoxins, interferons, new cytokines, and chemokines, Cytokine provides comprehensive coverage of cytokines and their mechanisms of actions, 12 times a year by publishing original high quality refereed scientific papers from prominent investigators in both the academic and industrial sectors. We will publish 3 major types of manuscripts: 1) Original manuscripts describing research results. 2) Basic and clinical reviews describing cytokine actions and regulation. 3) Short commentaries/perspectives on recently published aspects of cytokines, pathogenesis and clinical results.