G[alpha]-interacting Vesicle Associated Protein Mediates Cell Survival During Endoplasmic Reticulum Stress

Abstract: Endoplasmic reticulum (ER) stress is a form of cellular stress that is experienced both under normal physiological conditions such as in professional secretory cells and disease states such as cancer, diabetes and neurodegeneration. Upon facing ER stress, cells initially try to restore normal function by activating a conserved signaling pathway called the Unfolded Protein Response (UPR). However, if the stress is overwhelming and cells are not able to recover within a reasonable time frame, the UPR ultimately commits cells to apoptosis. How cells make this life-or-death decision remains an exciting yet poorly understood phenomenon. Here, we show that G[alpha]-Interacting Vesicle associated protein (GIV), a multimodular signaling protein, helps promote cell survival during ER stress via activation of the Akt pathway. HeLa cells treated with various ER stressors activate the Akt pathway and this activation is significantly diminished upon shRNA-mediated depletion of GIV. Furthermore, GIV-depleted cells show an increase in levels of CCAAT/enhancer binding protein homologous protein (CHOP) - a pro-apoptotic transcription factor and a significant reduction in cell survival during ER stress. Together, these findings suggest that GIV may play an important role in helping cells survive ER stress in HeLa cells.