UC San Diego

Protein quality control is vital for maintaining cellular health and preventing stress. Eukaryotic cells are equipped with protein quality controls pathways to identify and remove misfolded proteins. The ubiquitin proteasome system in one of the major pathways that cells use to target and degrade aberrant proteins. At the endoplasmic reticulum, a pathway called endoplasmic reticulum associated degradation utilizes the ubiquitin proteasome system for degradation of misfolded proteins. In yeast, a protein called Dfm1 is required for the degradation of misfolded membrane proteins at the endoplasmic reticulum. Dfm1 is a member of the rhomboid protein family. This is a family of integral membrane proteins including both proteases and pseudoproteases. Dfm1 is a rhomboid pseudoprotease. While rhomboid pseudoproteases may lack a catalytic site, they are still involved in a wide array of biological processes.

Protein aggregates are a common feature of diseased and aged cells. Membrane proteins comprise a quarter of the proteome, and yet, it is not well understood how aggregation of membrane proteins is regulated and what effects these aggregates can have on cellular health. This dissertation describes our original research demonstrating Dfm1 has a chaperone-like activity that influences misfolded membrane protein aggregation. We establish that this function of Dfm1 does not require recruitment of the ATPase Cdc48 and it is distinct from Dfm1’s previously identified function in dislocating misfolded membrane proteins to the cytosol for degradation. Additionally, we assess the cellular impacts of misfolded membrane proteins in the absence of Dfm1 and determine that misfolded membrane proteins are toxic to cells in the absence of Dfm1 and cause disruptions to proteasomal and ubiquitin homeostasis.