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<p>Glioblastoma (GBM) is one of the most aggressive and treatment-refractory brain tumors. Temozolomide (TMZ) remains the standard chemotherapeutic agent but is frequently compromised by DNA-repair mechanisms, whereas tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis only in a subset of tumors due to strong intrinsic resistance. Here, we identify the Mu-2-related death-inducing gene (MUDENG/MuD) as the µ-subunit of adaptor protein complex 5 (AP5M1). TurboID-based proximity labeling revealed reproducible interactions with AP5B1 and AP5M1 subunits, as well as additional associations with AP1–3 complexes and nuclear proteins involved in cell-cycle regulation. These findings establish MuD as a multifunctional component of the AP5 complex that modulates cell-fate signaling in a context-dependent manner. Using MuD-mutant GBM cell lines, we demonstrate that MuD suppresses TRAIL-induced apoptosis by interfering with extrinsic and intrinsic pathways downstream of Bid, whereas it promotes TMZ-induced cytotoxicity through p53-dependent cell-cycle control and DNA-damage responses. Gene set enrichment analysis (GSEA) and functional profiling further revealed distinct MuD-associated interactomes linked to receptor endocytosis and genotoxic-stress pathways. Together, these results uncover opposing roles of MuD in TRAIL- and TMZ-mediated cell death, with MuD suppressing apoptotic signaling in response to TRAIL while modulating p53-dependent genotoxic stress responses that influence TMZ-induced cytotoxicity in glioblastoma.</p>

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MUDENG, a component of adaptor complex 5, mediates TRAIL- and TMZ-triggered apoptosis in glioblastoma (GBM) via multiple pathways

  • 期刊论文

  • 发表日期：

    2026年3月31日

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  • Juhyun Shin,
  • Yoon-Mi Lee,
  • SooHyun Jung,
  • Sumin Han,
  • Arti Nile,
  • Su-Jin Kim,
  • Sang-Won Lee,
  • Jae-wook Oh

摘要

Glioblastoma (GBM) is one of the most aggressive and treatment-refractory brain tumors. Temozolomide (TMZ) remains the standard chemotherapeutic agent but is frequently compromised by DNA-repair mechanisms, whereas tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis only in a subset of tumors due to strong intrinsic resistance. Here, we identify the Mu-2-related death-inducing gene (MUDENG/MuD) as the µ-subunit of adaptor protein complex 5 (AP5M1). TurboID-based proximity labeling revealed reproducible interactions with AP5B1 and AP5M1 subunits, as well as additional associations with AP1–3 complexes and nuclear proteins involved in cell-cycle regulation. These findings establish MuD as a multifunctional component of the AP5 complex that modulates cell-fate signaling in a context-dependent manner. Using MuD-mutant GBM cell lines, we demonstrate that MuD suppresses TRAIL-induced apoptosis by interfering with extrinsic and intrinsic pathways downstream of Bid, whereas it promotes TMZ-induced cytotoxicity through p53-dependent cell-cycle control and DNA-damage responses. Gene set enrichment analysis (GSEA) and functional profiling further revealed distinct MuD-associated interactomes linked to receptor endocytosis and genotoxic-stress pathways. Together, these results uncover opposing roles of MuD in TRAIL- and TMZ-mediated cell death, with MuD suppressing apoptotic signaling in response to TRAIL while modulating p53-dependent genotoxic stress responses that influence TMZ-induced cytotoxicity in glioblastoma.