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

作者：Yiting Feng, Xiaochen Cheng, Yuanzhe Yang, Chuanjin Liu, Shi Yu, Xiaopeng Qi, Wei Zhao, Bingyu Liu, Tian Chen, Chengjiang Gao · 发表于：Cell Reports · 年份：2025 · DOI：10.1016/j.celrep.2025.115972 · 被引用次数：3 · 研究领域：interferon and immune responses、Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Ubiquitin and proteasome pathways

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.