TBK1 phagosomal recruitment enhances antifungal immunity via positive feedback regulation with SRC.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-07-08 DOI:10.1016/j.celrep.2025.115972

Yiting Feng, Xiaochen Cheng, Yuanzhe Yang, Chuanjin Liu, Yu Shi, Xiaopeng Qi, Wei Zhao, Bingyu Liu, Tian Chen, Chengjiang Gao

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引用次数: 0

Abstract

TANK-binding kinase 1 (TBK1) is a versatile serine/threonine protein kinase that is mainly recognized for its canonical role in antiviral immunity through interferon induction. Here, we report a previously uncharacterized function for TBK1 in antifungal defense. Using proteomic analysis, we identified TBK1 as a phagosome-directed protein after fungal infection, and biochemical analysis revealed that TBK1 is directly recruited to the phagosome by SHP2 in a process driven by SRC-mediated phosphorylation. This recruitment facilitates TBK1 aggregation and trans-autophosphorylation at the phagosome. Activated TBK1 then phosphorylates SRC at serine 17, a prerequisite for the full activation of SRC, thereby establishing a robust positive feedback loop among SRC, SHP2, and TBK1. Consistently, SRC-mediated antifungal signaling and production of proinflammatory cytokines and chemokines were significantly impaired in mouse bone marrow-derived macrophages (BMDMs) lacking TBK1. Myeloid Tbk1-deficient mice exhibited greater susceptibility to systemic Candida albicans infection. Overall, our findings reveal a critical role for TBK1 in antifungal immunity and highlight its potential as a therapeutic target for combating fungal pathogens.

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TBK1吞噬体募集通过SRC的正反馈调节增强抗真菌免疫。

TANK-binding kinase 1 （TBK1）是一种多用途丝氨酸/苏氨酸蛋白激酶，主要通过干扰素诱导在抗病毒免疫中发挥典型作用。在这里，我们报告了TBK1在抗真菌防御中的一个以前未被描述的功能。通过蛋白质组学分析，我们发现TBK1在真菌感染后是一个吞噬体导向蛋白，生化分析表明TBK1在src介导的磷酸化驱动下被SHP2直接招募到吞噬体。这种招募促进了TBK1的聚集和吞噬体的反式自磷酸化。激活的TBK1随后磷酸化SRC的丝氨酸17，这是SRC完全激活的先决条件，从而在SRC、SHP2和TBK1之间建立一个强大的正反馈回路。在缺乏TBK1的小鼠骨髓源性巨噬细胞（bmdm）中，src介导的抗真菌信号和促炎细胞因子和趋化因子的产生均明显受损。骨髓tbk1缺陷小鼠对全身白色念珠菌感染表现出更大的易感性。总之，我们的研究结果揭示了TBK1在抗真菌免疫中的关键作用，并突出了其作为对抗真菌病原体的治疗靶点的潜力。

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.