Endoplasmic Reticulum Stress: Its Role in Disease and Novel Prospects for Therapy

Figure 1

Triggers of ER stress and the yin-yang balance of cell survival versus cell death. A great variety of conditions and pharmacological compounds can disturb ER homeostasis, leading to ER stress and the accumulation of unfolded and misfolded proteins. In response, ER stress signaling pathways stimulate pro-survival efforts to either neutralize the stressful insult or adapt to it. GRP78 plays a key role in the cell’s attempt to adapt and survive. In contrast, if ER stress is too severe, the pro-apoptotic module of this cellular system gains dominance and shifts the balance towards cell death. CHOP represents a central executor of this latter process. In essence, these opposing processes of cell death versus survival are reflective of the yin-yang (shadow and light) concept of Chinese philosophy, where seemingly contrary forces are interconnected and interdependent as part of a greater whole. Although many other components participate in balancing the cell’s yin-yang response to ER stress, the opposing efforts of prosurvival (yang) GRP78 and proapoptotic (yin) CHOP represent important tenets of this struggle; as well, their expression levels are being used as convenient markers and readouts as to the ER stress status of cells. Details of GRP78 and CHOP functions are presented in Figures 2 and 3, respectively.