Before a protein can play its destined part in a cell, it must successfully complete a few fundamental processes: correct folding into its destined three-dimensional structure, integration into its larger protein complex (where applicable) and completion of any additional chemical alterations. Such posttranslational modifications entail for example the addition of disulfide, glycans or lipids. But what happens if something during these processes goes wrong? What if a protein is not properly translated, folded, assembled into complexes, or chemically modified? The resulting dysfunctional proteins, if left unchecked, pose a serious threat to a cell’s health and ultimately life. It is thus of paramount importance for the cell to control and maintain the quality of its protein production. In fact, many human diseases are linked to problems in this cellular quality control process that impede proper removal of dysfunctional proteins or permit their accumulation and aggregation.

   The long-term aim of our group’s research is to understand the processes that control and maintain the quality of proteins produced in the endoplasmic reticulum (ER). The cell’s ER is responsible for the proper folding and chemical modification of a third of all eukaryotic proteins including all membrane-embedded and secreted proteins. Also, certain posttranslational modifications such as disulfide or glycans addition are exclusive to the ER. But what happens to all the dysfunctional proteins that are unavoidably produced there as well? They are processed by the ER-associated degradation (ERAD) pathway. Embedded in the ER membrane, the multi-protein ERAD complex is tasked with identifying, unfolding, and transporting corrupt proteins into the cytoplasm, where they are passed on to the machinery of the proteasome.

Our lab’s research into the cellular management of protein fidelity focuses on the identification, unfolding, and translocation of dysfunctional proteins by the ERAD. We want to understand how these key steps are regulated and controlled because it provides a potential avenue to precisely modify the ERAD’s response instead of just terminating it. This marks the proteins involved in these steps as the ideal targets to selectively manipulate protein degradation. Such therapeutic approaches have great potential for diseases where for example protein overproduction -like in cancer- is a key issue or where specific proteins form detrimental aggregates as in certain forms of amyotrophic lateral sclerosis (ALS).  

In our current projects, we focus specifically on the important ERAD proteins derlin, selenoprotein K (SELENOK) and selenoprotein S (SELENOS, VIMP), their interactions with each other as well as other proteins and how their actions and interactions contribute to ERAD functions and their control. The specific research directions are described in more detail below.

  The very core of the ERAD complex is formed by ubiquitin ligases (enzymes that tag ubiquitin to proteins) and the membrane protein derlin. Like all members of the family of rhomboid proteins, derlin can both recognize proteins inside the lipid bilayers and locally alter the properties of the membrane. Because of these key features, rhomboid proteins are often involved in the regulation of membrane proteins. The specifics of these regulatory processes, 

   Selenoprotein K (SELENOK) is a small intrinsically disordered signaling protein. It is involved both in protein quality control but also in the attachment of hydrophobic chains to proteins which targets them to membranes. Because selenoprotein K has the rare amino acid selenocysteine, it is most likely an enzyme. Like other proteins we study, it is embedded in the ER membrane. Unpublished results from our group show that selenoprotein K catalyzes the cleavage of its own peptide bond. Interestingly,the cleavage releases the selenocysteine-containing segment which could terminate the proteins enzymatic activity. The fact that the same selenocysteine-containing segment is also cleaved by a different cellular protease during signal transduction suggest a regulatory function of selenoprotein K’s autoproteolytic activity.