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Tumor susceptibility gene 101 regulates predisposition to apoptosis via ESCRT machinery accessory proteins

Zenia Kaul1, Oishee Chakrabarti2

  • 1Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata 700064, India.

Molecular Biology of the Cell
|May 26, 2017
PubMed

Insights

TSG101, an ESCRT-I protein, mitigates ER stress-induced apoptosis by interacting with ALIX. Its deficiency, alongside increased ALIX and ALG-2, promotes cell death, a process implicated in neurodegeneration.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Neuroscience

Background:

  • ESCRT proteins are involved in various cellular functions, including apoptosis, but their precise roles remain unclear.
  • Mahogunin RING finger 1 (MGRN1) deficiency is linked to neurodegeneration and developmental mortality, suggesting a role in cell viability.
  • The ESCRT-I protein TSG101's function in apoptosis is not fully understood.

Purpose of the Study:

  • To investigate the role of TSG101 in mitigating ER stress-mediated apoptosis.
  • To elucidate the molecular mechanisms underlying TSG101's protective function against apoptosis.
  • To explore the involvement of TSG101, ALIX, and ALG-2 in ER stress-induced cell death.

Main Methods:

  • Investigated the interaction between TSG101, ALIX, and ALG-2 in cellular models.
  • Analyzed the effects of MGRN1 deficiency and TSG101 modulation on apoptosis.
  • Assessed ER stress markers, caspase activation, and calcium homeostasis.
  • Examined the role of prion protein (CtmPrP) in ER stress and apoptosis.

Main Results:

  • TSG101 directly mitigates ER stress-mediated apoptosis.
  • TSG101-ALIX association prevents apoptosis, while ALIX-ALG-2 interaction promotes it.
  • Altered calcium homeostasis and increased ALIX/ALG-2 levels are crucial for ER stress-induced apoptosis via caspase 4/12 activation.
  • Prion protein CtmPrP exacerbates ER stress and apoptosis, effects rescued by TSG101 overexpression.

Conclusions:

  • TSG101 plays a critical role in preventing ER stress-induced apoptosis.
  • The balance between TSG101-ALIX and ALIX-ALG-2 interactions dictates cell fate.
  • Dysregulation of these pathways, potentially involving prion proteins, contributes to neurodegeneration and developmental issues.

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