Figure 2.

Signal transduction events associated with ER stress. The accumulation of misfolded proteins and disruption of Ca²⁺ homeostasis in the ER disrupt ER function leading to ER stress. The unfolded protein response (UPR) is initiated as a response to this stress, where GRP78, PERK, IRE1, and ATF6 play a central role. However, there might be more unknown mediators of ER stress. The cell initially tries to resolve the ER stress and restore normal cell function by halting protein synthesis and activation of several ER Stress Response (ERSR) adaptation genes, which include chaperones and proteins of the ER-associated degradation (ERAD) system. However, prolonged ER stress leads to the activation of the “alarm response”, leading to cell damage, dysfunction, and finally apoptosis.