The Expanding Roles of PACS-1 and PACS-2 in Cellular Physiology: Beyond Vesicular Protein Trafficking
Abstract
Phosphofurin acidic cluster sorting (PACS) proteins 1 and 2 are essential components of the cytoplasmic protein trafficking machinery. Recent reports have described novel roles for PACS-1 in the nucleus. Here, we defined the mechanism of PACS-1 nucleocytoplasmic shuttling by identifying the interactions of PACS-1 with nuclear transport receptors and mapping its nuclear localization/export signals. Furthermore, we described the molecular basis and the subcellular location of the interactions between PACS-1 and RNA-binding proteins, including the cellular polypyrimidine tract-binding protein 1 and the HIV-1 Rev protein. In addition, we characterized the poorly understood biochemical properties of a PACS-2 E209K mutation involved in neurodevelopmental epilepsy. Specifically, we elucidated that PACS-2 E209K had a longer half-life and enhanced interaction with the 14-3-3ε protein. The PACS-2 E209K mutation also increased susceptibility to staurosporine-induced apoptosis. Overall, this thesis extends our understanding of the PACS proteins and expands their roles in RNA metabolism and cellular stress responses.