Life sciences · 2025
TRAF2 mediates Wnt-induced β-catenin nuclear translocation by associating with the nuclear pore complex.
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Yang Min, Xuan Ying, Hao Piliang, Li Yushu, Zhang Chengqian, Zhao Weiwei, Zhang Yiyuan, Zhang Xue, Zhou Xianglian, Zhu Hongyan, Li Huihui, Yang Yan, Wang Jiaqi, Yan Rong, Qu Yi, Ke Xisong
Аннотация
AIMS: Colorectal cancer (CRC), driven by Wnt/β-catenin hyperactivation, relies on nuclear import of β-catenin, but the underlying mechanism is not fully clarified. Given that tumor necrosis factor receptor-associated factor 2 (TRAF2) is a positive regulator of Wnt signaling by directly interacting with β-catenin, we aim to demonstrate the role of TRAF2 in Wnt-induced β-catenin nuclear translocation.
MATERIALS AND METHODS: Wild-type and TRAF2 knockout cells (generated via CRISPR-Cas9) were utilized to validate the role of TRAF2 in β-catenin nuclear translocation through immunofluorescence and nucleoplasm separation assay. Proteomic profiling of TRAF2 condensates and interactomes was performed to identify proteins linked to nucleocytoplasmic transport. The interactions among TRAF2, β-catenin, nucleoporins (Nups) and B-cell lymphoma 9 (BCL9), as well as the inhibitory effects of small molecule liquidambaric acid (LDA) on these interactions were confirmed using proximity ligation assay (PLA), fluorescence resonance energy transfer (FRET), and co-immunoprecipitation (Co-IP) in cellular models and small intestine of mice.
KEY FINDINGS: TRAF2 is required for Wnt-induced β-catenin nuclear translocation. TRAF2 interacts with numerous Nups within the nuclear pore complex (NPC), and is upregulated upon Wnt stimulation. In the small intestine of mice, TRAF2/Nups interaction is mainly detected in the crypts-regions known to harbor colorectal cancer stem cells, as well as in APCmin/+ intestinal organoids. Of note, TRAF2 is indispensable for β-catenin interaction with Nups and the known chaperone BCL9. Finally, LDA blocks TRAF2/Nups interaction, inhibiting β-catenin nuclear translocation.
SIGNIFICANCE: This study unveils TRAF2-mediated nucleocytoplasmic transport as a druggable mechanism, advancing targeted therapies against Wnt-driven colorectal cancers.
MATERIALS AND METHODS: Wild-type and TRAF2 knockout cells (generated via CRISPR-Cas9) were utilized to validate the role of TRAF2 in β-catenin nuclear translocation through immunofluorescence and nucleoplasm separation assay. Proteomic profiling of TRAF2 condensates and interactomes was performed to identify proteins linked to nucleocytoplasmic transport. The interactions among TRAF2, β-catenin, nucleoporins (Nups) and B-cell lymphoma 9 (BCL9), as well as the inhibitory effects of small molecule liquidambaric acid (LDA) on these interactions were confirmed using proximity ligation assay (PLA), fluorescence resonance energy transfer (FRET), and co-immunoprecipitation (Co-IP) in cellular models and small intestine of mice.
KEY FINDINGS: TRAF2 is required for Wnt-induced β-catenin nuclear translocation. TRAF2 interacts with numerous Nups within the nuclear pore complex (NPC), and is upregulated upon Wnt stimulation. In the small intestine of mice, TRAF2/Nups interaction is mainly detected in the crypts-regions known to harbor colorectal cancer stem cells, as well as in APCmin/+ intestinal organoids. Of note, TRAF2 is indispensable for β-catenin interaction with Nups and the known chaperone BCL9. Finally, LDA blocks TRAF2/Nups interaction, inhibiting β-catenin nuclear translocation.
SIGNIFICANCE: This study unveils TRAF2-mediated nucleocytoplasmic transport as a druggable mechanism, advancing targeted therapies against Wnt-driven colorectal cancers.