? ? In eukaryotic cells, proteins destined for the cell surface or for the external milieu are first translocated into the endoplasmic reticulum (ER) where initial protein folding and modifications occur that are essential for the protein to attain its appropriate functional conformation prior to transit to the cell surface. It has long been known that mutations in the primary amino acid sequence cause protein misfolding and contribute to disease pathogenesis. However, it is now becoming evident that diseases are not simply a result of protein loss of function, but rather frequently involve cellular processes that ? accommodate protein misfolding. Cells adapt to the accumulation of misfolded proteins in the ER by regulation at several fundamental cellular processes including gene expression, mRNA translation, and protein degradation. We have now experienced significant breakthroughs in our understanding about how cells coordinate these adaptive responses. If adaptation is not adequate, cells enter an apoptotic death pathway. In addition, recent studies indicate that protein misfolding not only results from gene ? mutations but also arises as a consequence of a variety of environmental insults ranging from altered metabolism, viral infection, hypoxia, oxidative stress, hypercholesterolemia, hypoglycemia, etc. Finally, many highly differentiated cell types, such as pancreatic beta cells and plasma cells, require signaling pathways to properly coordinate protein expression and secretion with the ER protein folding capacity. As we understand more about the adaptive and apoptotic responses to protein misfolding in the ER, it is evident that these events contribute to the pathology of numerous disease states. This conference ? will focus on a novel genetic, biochemical, and cell biological approaches to unravel the complexities of protein biosynthesis, folding, degradation, and cellular responses to misfolded protein accumulation in the early secretory pathway. Identifying the mechanisms by which cells adapt and succumb to protein folding defects will have tremendous impact on a variety of diseases including Alzheimer's disease, cardiovascular disease, diabetes, infectious disease, and cancer. Understanding the fundamental processes of how wild-type and mutant proteins fold can be exploited to develop therapeutically useful inhibitors or activators for these processes to target pathologies ranging from cancer, infection and immunological disorders, metabolic diseases, and genetic diseases. ? ? ?