TBK1 is a signaling hub in coordinating stress-adaptive mechanisms in head and neck cancer progression

作者：Kim HJ, Kim HJ, Kim SY, Roh J, Yun JH, Kim CH · 发表于：Autophagy · 年份：2025 · DOI：10.1080/15548627.2025.2481661 · 被引用次数：93 · 研究领域：Head and Neck Neoplasms、Protein Serine-Threonine Kinases、Signal Transduction、Stress, Physiological、Humans、Autophagy、Cell Line, Tumor、Animals、Disease Progression、Stress Granules、Mice、Ubiquitination

Tumorigenesis is closely linked to the ability of cancer cells to activate stress-adaptive mechanisms in response to various cellular stressors. Stress granules (SGs) play a crucial role in promoting cancer cell survival, invasion, and treatment resistance, and influence tumor immune escape by protecting essential mRNAs involved in cell metabolism, signaling, and stress responses. TBK1 (TANK binding kinase 1) functions in antiviral innate immunity, cell survival, and proliferation in both the tumor microenvironment and tumor cells. Here, we report that MUL1 loss results in the hyperactivation of TBK1 in both HNC cells and tissues. Mechanistically, under proteotoxic stress induced by proteasomal inhibition, HSP90 inhibition, or Ub+ stress, MUL1 promotes the degradation of active TBK1 through K48-linked ubiquitination at lysine 584. Furthermore, TBK1 facilitates autophagosome-lysosome fusion and phosphorylates SQSTM1, regulating selective macroautophagic/autophagic clearance in HNC cells. TBK1 is required for SG formation and cellular protection. Moreover, we found that MAP1LC3B is partially localized within SGs. TBK1 depletion enhances the sensitivity of HNC cells to cisplatin-induced cell death. GSK8612, a novel TBK1 inhibitor, significantly inhibits HNC tumorigenesis in xenografts. In summary, our study reveals that TBK1 facilitates the rapid removal of ubiquitinated proteins within the cell through protective autophagy under stress conditions and assists SG formation throug...