在核膜上一個新的LINC複合體成員Kuduk之研究

A Novel Partner of LINC Complex,Kuduk, at the Nuclear Envelope

丁肇瑩(Zhao-Ying Ding)

指導教授 ： 黃敏郎

國立中正大學/理學院/生命科學系分子生物研究所/博士(2014年)

摘要

核膜是細胞質及核質間的一個屏障，而且對細胞的功能來說是很重要的。核膜蛋白突變會導致人類疾病。在核膜上，連結細胞核骨架及細胞質骨架的(LINC)複合體是由分別在外層核膜的KASH 結構功能域蛋白及內層核膜的SUN結構功能域蛋白所構成。LINC 複合體參與許多生物體的發育過程，當LINC複合體突變時，會導致疾病，例如: 關節彎曲症、Emery-Dreifuss 肌肉萎縮症。然而，對於LINC 複合體如何被調控還不清楚。我們發現一個果蠅的膜蛋白Kud位在核膜，跟KASH 結構功能域蛋白有物理性交互作用。失去kud導致KASH 結構功能域蛋白Klar增加、細胞凋亡、細胞變小及核運輸缺陷。在kud 突變細胞減少LINC 複合體蛋白可拯救細胞凋亡。在人類細胞，Kud的人類同源蛋白TMEM258也與KASH 結構功能域蛋白有交互作用。大量表現TMEM258可拯救在kud 突變細胞的細胞凋亡，代表TMEM258與Kud保有相似功能。從這些結果推測Kud是LINＣ複合體的一個新的連結成員，且可能調控LINC複合體。這些發現使我們對LINC複合體的調控有更新的了解，且可能有益於LINC複合體相關疾病的治療。

關鍵字

高基氏體 ； 核膜蛋白

並列摘要

The nuclear envelope (NE) is a barrier between the nucleoplasm and cytoplasm, and is crucial for the cellular functions. Mutations in NE resident proteins cause human diseases. At the NE, the linker of the nucleoskeleton and cytoskeleton (LINC) complexes composed of KASH and SUN domain proteins which resides at outer nuclear membrane and inner nuclear membrane, respectively.　LINC　complexes are involved in many developmental process of the various organisams. The mutations of LINC components cause the diseases, such as arthrogryposis, and Emery-Dreifuss muscular dystrophy (EDMD). However, it is unclear how the LINC complexes are regulated. Here, we found that a Drosophila membrane protein, Kud, localized at NE, and physically interacts with KASH domain protein. Loss of kud caused the increased KASH domain protein Klar, the apoptosis, reduced cell size, and the nuclear transport defect. Reduction in the LINC components rescue the apoptosis in kud mutant cells. In human cells, the Kud’s human ortholog, TMEM258 also interacts with KASH domain proteins. The overexpression of TMEM258 rescues the apoptosis in kud mutant cells, indicating the functional conservations. These data suggest that Kud is a novel binding partner of the LINC complex, and could regulate the LINC complex. The findings bring new insights of how LINC complex are regulated and could be helpful the treatments of the related diseases.

並列關鍵字

LINC complex ； Nuclear envelope ； Kud

參考文獻

Franke, A., McGovern, D.P., Barrett, J.C., Wang, K., Radford-Smith, G.L., Ahmad, T.,

Khatau, S.B., Hale, C.M., Stewart-Hutchinson, P.J., Patel, M.S., Stewart, C.L., Searson,

Gruenbaum, Y., Margalit, A., Goldman, R.D., Shumaker, D.K., and Wilson, K.L. (2005).

8. REFERENCES

arthrogryposis. Hum Mol Genet 18, 3462-3469.