Endoplasmic reticulum-associated protein degradation (ERAD)是重要的細胞機制之一，主要用以降解細胞中發生錯誤的蛋白。錯誤摺疊的蛋白在內質網(Endoplasmic reticulum, ER)被辨識後會經由胞器膜上的通道蛋白送至細胞質中，經泛化作用(Ubiquitination)後由蛋白酶體(proteasome)降解。在哺乳動物中Derlin-1被認為是內質網上重要的通道蛋白之一，會與其他同位於內質網膜上的蛋白形成通道複合物後協助錯誤折疊的蛋白送至細胞質中進行降解。在ERAD 的過程中，AAA-ATPase蛋白VCP會將錯誤摺疊的蛋白帶往蛋白酶體進行降解。VCP本身在細胞中參與多項細胞功能的調控，其所扮演的角色取決於與之結合的輔因子(cofactor)。實驗室先前研究中已發現在果蠅中Derlin-1的過量表現會產生眼睛表面粗糙的表現型，而該表現型已證實與ERAD途徑受阻有關；但同時過量表現VCP或TER94(為果蠅中的VCP同源蛋白)則可抑制Derlin-1對果蠅眼睛所造成的損害，因此可從果蠅遺傳實驗中推測Derlin-1與TER94/VCP間相互調控的關聯性。在本篇研究中，我們則進一步利用分子實驗證實Derlin-1與TER94/VCP蛋白質會有直接的相互作用。此外，Derlin-1的同系蛋白Derlin-2在之前研究中也被認為與ERAD途徑有關，因此我們亦將在果蠅遺傳實驗與分子實驗中探討Derlin-2蛋白在ERAD途徑中所扮演的角色。

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.

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