Hendershot: Protein folding in the secretory pathway and the response of cells to alterations in the ER environment during normal and pathological conditions

Nearly all cell surface and secreted proteins are synthesized in the endoplasmic reticulum (ER), an organelle that possesses an oxidizing environment and contains millimolar concentrations of partially folded proteins and of calcium. A number of resident ER proteins, known as molecular chaperones, have been identified that both facilitate proper protein folding and serve to detect improperly folded proteins and target them for degradation. Adverse physiological or chemical conditions encountered during normal cellular growth often alter the environment of the ER and negatively affect protein biosynthesis in this organelle. This leads to an accumulation of unfolded proteins in this organelle, which activates a signal transduction pathway termed the unfolded protein response (UPR).  This response serves to protect the cell and restore homeostasis to the ER by transcriptionally up-regulating ER chaperones, transiently inhibiting cap-dependent translation, and increasing the degradative capacity of the cell. Our studies reveal that the ER chaperone BiP plays a critical role in aiding the maturation of nascent secretory pathway proteins as well as in identifying and targeting unfolded proteins for degradation. In addition, BiP is the key sensor for detecting abnormal folding in the ER and regulating the UPR signal transducers. We use a variety of molecular, biochemical, and cell biological methodologies to understand the mechanisms by which molecular chaperones are able contribute to both the maturation and the disposal of proteins in the ER and to understand the signal transduction pathways that control the transcription of the chaperone genes. Many genetic diseases are caused by a point mutation in a particular protein that alters its folding, assembly, and/or transport through the cell. Thus, knowledge of the cellular processes that assist and monitor the synthesis of nascent proteins is important to understanding these diseases and identifying potential mechanisms for intervention. During solid tumor cell growth, cells encounter conditions of low oxygen and nutrients, which activates the UPR in these cells. This serves to protect neoplastic cells from their insufficient environment and to alter their sensitivity to chemotherapeutic agents, thus interfering with therapy. Identification of the UPR components that are responsible for this protection may provide targets for improving treatment of solid tumors.