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

ESCRT proteins are implicated in myriad cellular processes, including endosome formation, fusion of autophagosomes/amphisomes with lysosomes, and apoptosis. The role played by these proteins in either facilitating or protecting against apoptosis is unclear. In this study, while trying to understand how deficiency of Mahogunin RING finger 1 (MGRN1) affects cell viability, we uncovered a novel role for its interactor, the ESCRT-I protein TSG101: it directly participates in mitigating ER stress-mediated apoptosis. The association of TSG101 with ALIX prevents predisposition to apoptosis, whereas ALIX-ALG-2 interaction favors a death phenotype. Altered Ca2+ homeostasis in cells and a simultaneous increase in the protein levels of ALIX and ALG-2 are required to elicit apoptosis by activating ER stress-associated caspase 4/12. We further demonstrate that in the presence of membrane-associated, disease-causing prion protein (PrP)-Pr-Ctm, increased ALIX and ALG-2 levels are detected along with ER stress markers and associated caspases in transgenic brain lysates and cells. These effects were rescued by overexpression of TSG101. This is significant because MGRN1 deficiency is closely associated with neurodegeneration and prenatal and neonatal mortality, which could be due to excess cell death in selected brain regions or myocardial apoptosis during embryonic development.