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TSG101 depletion dysregulates mitochondria and PML NBs, triggering MAD2-overexpressing interphase cell death (MOID)

Yao Xi1,2, Rui Xu1,2, Shengnan Chen1,2

  • 1National Resource Center for Mutant Mice, MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, 210061, China.

Cell Death & Disease
|November 17, 2024
PubMed

Insights

Overexpression of mitotic arrest deficiency 2 (MAD2) combined with depletion of tumor susceptibility gene 101 (TSG101) triggers a novel cell death pathway called MOID. This process involves mitochondrial dysfunction and PML nuclear bodies, impacting cancer cell survival.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Research

Background:

  • Overexpression of mitotic arrest deficiency 2 (MAD2/MAD2L1), a key spindle assembly checkpoint (SAC) component, is implicated in various cancers.
  • The role of tumor susceptibility gene 101 (TSG101) in conjunction with MAD2 overexpression in cancer cell death remains largely unexplored.

Purpose of the Study:

  • To investigate the novel cell death mechanism, termed MAD2-overexpressing interphase cell death (MOID), induced by TSG101 depletion in MAD2-overexpressing cancer cells.
  • To elucidate the molecular pathways and protein interactions governing MOID, focusing on the roles of PML, DAXX, and mitochondrial signaling.

Main Methods:

  • Utilized cell culture models with MAD2 overexpression and TSG101 depletion to induce and study MOID.
  • Investigated the involvement of PML, DAXX, AIFM1, and mitochondrial release in MOID induction.
  • Analyzed protein localization, stability, phosphorylation, and deSUMOylation of key proteins including MAD2, TSG101, and PML.

Main Results:

  • TSG101 depletion causes synthetic dosage lethality (SDL) in MAD2-overexpressing cells, leading to MOID.
  • MOID induction is dependent on PML and DAXX-mediated mitochondrial apoptosis-inducing factor 1 (AIFM1) release.
  • MAD2, TSG101, and the AIF-PML-DAXX axis regulate mitochondria, PML nuclear bodies (NBs), and autophagy, with interdependent protein stability crucial for cell survival.
  • Loss of TSG101 C-terminal phosphorylation and closed (C-)MAD2 overexpression contribute to MOID.
  • PML release from NBs via deSUMOylation is critical for MOID induction.

Conclusions:

  • MOID represents a novel synthetic dosage lethality pathway triggered by the interplay between MAD2 overexpression and TSG101 loss.
  • The AIF-PML-DAXX axis and mitochondrial integrity are central to MOID execution.
  • PML nuclear bodies and protein post-translational modifications, including TSG101 phosphorylation and PML deSUMOylation, are critical regulators of this cell death pathway.

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