Special LMNN Seminar - Identification of an ER-resident receptor tyrosine kinase that regulates proteostasis

Nearly 70% of the energy of a eukaryotic cell is devoted to protein synthesis. Thus, our cells have evolved a complex machinery that handles the proteome. The homeostatic balance of protein synthesis, quality control, trafficking and degradation is referred to as proteostasis. Most of what we know about the regulation of proteostasis is based on how cells deal with misfolded or toxic proteins through a process called the Unfolded Protein Response (UPR). The main function of the UPR is to stop protein synthesis and to increase the efficiency of folded and degradation. While the UPR is a fairly well understood process, less is known about how cells deal with fluctuations of folded proteins. The aforementioned responses of the UPR seem inadequate to help the endoplasmic reticulum (ER) to deal with folded proteins. In my talk I will show evidence that we have identified and ER-resident receptor tyrosine kinase that senses folded proteins and thereby regulates proteostasis. I will discuss possibilities that this is part of a general response that we might call the Folded Protein Response (FPR). Finally, I will show how the FPR is relevant for understanding diseases that are characterized by changes in the load of folded proteins such as multiple myeloma.