Ubx cofactors are required in San1-dependent nuclear protein quality control

Abstract

Accumulation of misfolded proteins in the cell are linked to many human diseases. To ensure optimal cellular physiology, the cell has compartmentalized the protein quality control system (PQC). As a compartment, the nucleus is unique in two important ways. First, the nucleus is the home of our genome. Second, unlike the cytoplasm, the nucleus is a location for post synthetized proteins. Since several key activities such as DNA synthesis and repair occur in the nucleus, an important aspect of maintaining optimal nuclear function is to reduce the burden of misfolded proteins when they arise in the nucleus. Using the Saccharomyces cerevisiae as our model organism, we previously identified San1 as the E3 ubiquitin ligase which targets misfolded proteins for degradation. Our past studies also identified the AAA-ATPase Cdc48 to be another essential player that degrades nuclear misfolded protein in the San1 pathway. In the current study, my thesis work explores the players that assist Cdc48 to degrade nuclear misfolded proteins in the San1 pathway. We found Ubx1, Ubx4 and Ubx5 to regulate nuclear protein homeostasis. Our experiments reveal the Ubx cofactors to play distinct functional roles in maintaining a healthy nucleus.