Abstract
Endoplasmic reticulum-associated protein degradation (ERAD) is a cellular process for protein quality control through targeting ER misfolded proteins that designating in the secretory pathway for ubiquitination and subsequent proteasome degradation. In mammal, Derlin-1 (Der1-like domain family, member 1) is predicted as an ER transmembrane protein that involves in ERAD pathway with a putative function as retro-translocation channel. This process requires an AAA ATPase protein p97/VCP to remove the targeted protein from ER, and genetic studies have showed that p97/VCP is indispensable for ERAD. In a Drosophila model, overexpressing fly Derlin-1 cause eye rough phenotype in which could be specifically suppressed by overexpressing wild or mutant TER94 (fly p97/VCP homolog), suggesting a direct genetic link between Derlin-1 and TER94/VCP. In this study, I utilized biochemical and genetic studies to determine that the SHP domain at the C-terminus of Derlin-1 is critical for TER94 interaction. And I also demonstrated that N-domain of TER94/VCP is depended on interaction between Derlin-1 and TER94/VCP. Another Derlin family protein Derlin-2, which has been suggested to localize on ER membrane and involve in ERAD pathway, but nevertheless, little is known about its function in vivo. In this study, I begin to characterize the function of Derlin-2 in ERAD pathway by employing fly genetic and molecular assays. The preliminary data indicate Drosophila Derlin-2 may have distinct function or functional redundant in the ERAD pathway.