The endoplasmic reticulum (ER) produces the majority of proteins for a certain type of cell. Often, the building blocks of proteins do not fold properly. This leads to harmful proteins. These misfolded proteins damage essential cellular functions. Cells have a quality control process that eliminates misfolded proteins in the ER. This process is called ER-associated degradation (ERAD) or retrotranslocation. ERAD exports unwanted proteins into fluid within the cell. Here, other proteins will break them down. Defects in ERAD result in the accumulation of misfolded proteins. Such defects also cause ER stress. ER stress influences the development of diseases, including type 2 diabetes. Certain viruses also hijack ERAD. This destroys the folded cellular proteins that fight viruses. By destroying the proteins, these viruses evade immune system detection.
Our research group has made progress toward understanding how ERAD works. We identified an enzyme in intracellular fluid (p97). This enzyme drives the movement of misfolded protein components during ERAD. Our group also discovered a particular set of proteins embedded in the cell membrane that work together. They are called a membrane protein complex. This complex interacts with p97 and influences the transport of misfolded protein components. The central part of this complex is called Derlin-1. We believe Derlin-1 helps to form a channel to conduct misfolded protein components. We also uncovered a chaperone complex that keeps misfolded proteins dissolvable. This helps break down the misfolded proteins. We are currently investigating how p97 drives ERAD. Our group also studies p97’s other functions and interaction partners. Our research also examines how enzymes work together to break down misfolded ER proteins.