Protein Sorting and Organelle Biogenesis

Our research centers on two fundamental questions in cell biology: How do proteins become properly localized within a cell? Protein sorting is the fundamental process by which order and compartmentalization are achieved and maintained in living cells. As a paradigm, we study the pathways which allow certain classes of proteins to become selectively targeted to the endoplasmic reticulum (ER). Targeting to the ER is the first step in the secretory pathway of all eukaryotic cells. We aim at a precise molecular understanding of the signal recognition particle (SRP) and its receptor which function together as molecular adapters to couple protein synthesis and membrane translocation. At least three interacting GTPases are involved in the process. We also discovered and are characterizing alternative pathway(s) in yeast that allows proteins to become targeted the ER in the absence of SRP or its receptor. How do cells maintain the abundance of organelles in proper balance? Regulatory networks must exist that control organelle abundance as a prerequisite for cells to become and remain differentiated. We investigate the proliferation of the ER in response to the accumulation of misfolded proteins in its lumen. We discovered an ER transmembrane kinase in S. cerevisiae that regulates the genes of ER resident proteins and coordinates key enzymes involved in lipid biosynthesis. This suggests that the induction of ER contents is coupled to the biogenesis of new organelle membrane. It is likely that these findings in yeast can be applied directly to mammalian cells. We will expand these studies to include regulatory pathways that control the abundance of other organelles in differentiated cells.