TXLNA enhances TBK1 phosphorylation by suppressing PPM1B recruitment

In recent years, there has been a notable increase in cancer incidence and mortality, and immune abnormalities have been closely linked to malignancy development. TANK-binding kinase 1 (TBK1) is a non-classical IκB kinase that regulates interferon and NF-κB signaling pathways and plays a crucial role in innate immunity. Recent studies have shown high expression levels of TBK1 and increased activity in various tumor cells, suggesting its involvement in the development and progression of multiple cancers. Targeting TBK1 for tumor therapy may be a possibility. However, little is known about the abnormal activation and dynamic regulation of TBK1 in cancer. First, we utilized the BioID biotinylation technique combined with TMT-based quantitative proteomics to analyze the TBK1 interacting proteins. Our results revealed that TXLNA interacts with TBK1 and binds to the α-helical scaffold of TBK1. The expression of TXLNA could affect the S172 phosphorylation of TBK1. PPM1B is a phosphatase that can dephosphorylate TBK1 S172, so we used the APEX2 proximity labeling technique combined with TMT-based quantitative proteomics to explore the interacting proteins of PPM1B and search for the regulatory pathway of TXLNA on TBK1 phosphorylation. We found that PPM1B interacts with TXLNA. Based on these results, we further found that TXLNA impairs the binding of PPM1B to TBK1, inhibiting the dephosphorylation of TBK1 and contributing to the abnormal enhancement of TBK1 activity in cancer cells. This study sheds light on the potential mechanism of aberrant activation and dynamic regulation of TBK1 in tumors and provides a potential target for tumor therapy.