Endoplasmic Reticulum (ER) stress-induced cardiomyocyte dysfunction and death are thought to play a central role in the development of numerous cardiovascular diseases. Therefore, understanding the signaling networks that control programmed cell death triggered by ER stress is expected to provide valuable therapeutic targets. The ER stress pathway begins with activation of a tripartite of signal transduction pathways, collectively known as the Unfolded Protein Response (UPR), in an attempt to restore homeostasis. If the damage at the ER is too severe, however, then the UPR triggers apoptosis at the mitochondria through the BCL-2 family of cell death regulators. The signaling network that connects the ER stress to the BCL-2 death machinery has remained largely elusive. Addressing this point, we recently discovered that BOK, unlike its BCL-2 family homologues BAX and BAK, selectively regulates the apoptotic response to ER stress, but not other stimuli. Thus, the overall goal of this proposal is to define the mechanisms by which BOK transmits ER stress to promote apoptosis. Preliminary work supports a non-canonical function for BOK that largely occurs at the ER where it is bound to the inositol-3-phosphate (IP3R) calcium transporter. I propose a multidisciplinary approach that employs genetics, advanced imaging, and biochemistry to focus on the physiologic role of BOK in mediating ER-mitochondrial signaling in cardiomyocytes. In particular, we will examine (1) the finely resolved localization of BOK function, (2) calcium homeostasis and (3) the ER-mitochondria interface under normal and ER stress conditions. The proposed mechanistic dissection of BOK activity will integrate cellular physiology at the ER with the regulation of apoptosis by the BCL-2 family at the mitochondria. Understanding this pathway will likely yield valuable pharmacologic targets to promote cell survival in the face of extreme ER stress and thereby alleviate or eliminate the long term consequences of cell death in cardiovascular diseases.
Extreme stress destabilizes the delicate balance of an intricate signaling network that controls cell life and death and thus contributes too many human diseases, including heart disease. Embedded within this network is an enigmatic protein called BOK, which triggers cell death in a manner and method relevant to heart cells. This project will elucidate how BOK controls cell death and serve as a potential therapeutic target.
|Gross, Atan; Katz, Samuel G (2017) Non-apoptotic functions of BCL-2 family proteins. Cell Death Differ 24:1348-1358|