臺灣博碩士論文加值系統

中文摘要
D型肝炎病毒(hepatitis D virus ; HDV)可在肝細胞內繁殖，但必須與B型肝炎病毒(hepatitis B virus ; HBV)共同存在時才具備感染力。HDV是一個直徑36 nm的病毒顆粒，其內部包含一條單股、共價封閉的環形1.7 kb RNA基因體及大小兩種形式的delta抗原所構成。HDV能轉譯出來的蛋白質，具有大、小兩種型式；小型delta抗原(SDAg)及大型delta抗原(LDAg)，而LDAg只比SDAg在C端多了19個胺基酸。外套膜則由B型肝炎病毒(hepatitis B virus ; HBV)所提供的表面抗原(HBsAg)所構成，分別為大型表面抗原(L)，中型表面抗原(M)，小型表面抗原(S)。目前已知HBV大型表面抗原主要是負責HBV及HDV的感染(infection)，而小型表面抗原則足夠包裝HDV病毒顆粒，然而中型表面抗原的功能仍不清楚。LDAg在HDV的包裝及分泌上扮演重要的角色，其需被isoprenylation且負責與HBV的HBsAg作用。另一方面雖然LDAg已經證實會被磷酸化，而且磷酸化對於包裝與分泌似乎扮演較不重要的角色，但其對LDAg功能的影響並不是非常清楚，例如LDAg在細胞的分布及其他功能:如抑制HDV。
為了回答這些問題，本論文利用綠色螢光蛋白(green fluorescent protein; GFP)與不同型態的HDAg融合並以螢光顯微鏡，西方點墨法及北方點墨法加以觀察及探討其細胞內分佈和生化特性。得到的結果是: (i)縮減突變株D(1-88)-GFP會聚集在核質小點而D(1-163)-GFP則大部分都聚集於核仁，GFP-LD(31-214)和GFP-LD(31-214)M則均勻分布於細胞核，GFP-LD會分布於核仁及核質小點(nuclear speckle)，GFP-LDM則大部分分布於核仁，只有少部份位於核質小點 ; (ii)當LDAg或N端縮減突變株融合了GFP [亦即GFP-LD or GFP-LD (31-214)] 並不會影響其與HBsAg的作用; (iii)當LDAg C端的cystein被突變為serine時[亦即GFP-LDM or GFP-LD(31-214)M]則無法被HBsAg帶出細胞外; (iv) GFP-LD而非GFP-LD(31-214)可和SDAg作用並藉由HBsAg共同分泌至細胞外; (v)GFP-LD而非GFP-LD(31-214)具有抑制HDV RNA複製的功能; (vi)藉由觀察GFP-LD的暫時轉染細胞(transiently transfected cells)及進行細胞分裂的永久表現細胞株(permanent cells)可發現GFP-LD出現的順序為核質=>核仁=>核質小點。經由觀察GFP-LD及GFP-LDM在細胞核分布情形的差異加上以isoprenylation inhibitor (lovastatine)處理GFP-LD永久表現細胞株48 hr以上的結果，證明LDAg的isoprenylation對其在細胞核的分布有重要的影響。當以dichlororibofuranosyl benzimidazole (DRB ; casein kinase II inhibitor)或staurosporine (protein kinase C inhibitor)處理GFP-LD永久表現細胞株時可觀察到GFP-LD會從核仁移動到包含SC35的核質小點，並且在移除掉DRB後兩小時GFP-LD又會重回到核仁。若是以okazaic acid (phosphatase inhibitor)處理時會發現GFP-LD只出現在核仁而消失於核質小點。
在研究中型表面抗原(M-HBsAg)包裝HDV病毒顆粒所扮演的角色實驗中，發現中型表面抗原可獨自包裝HDV的LDAg也可經由LDAg帶出SDAg，但是並無法包裝HDV的ribonucleoprotein (RNP) complex。由於中型表面抗原不能包裝HDV RNP的這個發現可提供未來在研究HDV LDAg及RNP是如何與HBsAg相互作用上做為參考模式。

Abstract
Hepatitis D (delta) virus (HDV) is an infectious agent that propagates in hepatocytes only in the presence of hepatitis B virus (HBV). HDV is a 36-nm particle that includes a 1.7 kilobase, single-stranded, covalently closed circular RNA genome and two delta antigens, i. e., the small delta antigen (SDAg) and the large delta antigen (LDAg), which differ only with the latter having an additional 19 amino acids at the C-terminus. The envelope of HDV is composed of surface proteins of HBsAg i.e., the large (L), middle (M), and major/small (S) surface antigen. The L-HBsAg has been demonstrated to be required for both HBV and HDV infectivity while the S-HBsAg is sufficient for the HDV package. However, the function of M-HBsAg in HDV packaging is not well characterized. HDV requires the isoprenylated LDAg for interaction with HBsAgs to allow packaging and secretion out of the host cell. Phosphorylated LDAg has been found but, as yet, neither localization of LDAg within the nucleus nor any other function has been correlated with modification. To answer these questions, green fluorescent protein (GFP) was used to fuse various forms of HDAg and their distribution and biological properties were examined by fluorescent microscopy, Western and Northern blotting. The results indicated that (i) D(1-88)-GFP localizes only in the nuclear speckles (NS), D(1-163)-GFP in nucleolus, GFP-LD in both nucleolous and the NS, GFP-LDM (non-isoprenylation mutant) mostly in nucleolus but few in NS, but GFP-LD(31-214)[N-terminal deletion mutant] and GFP-LD(31-214)M with an even distribution in the nucleoplasm including the nucleolus; (ii) the additional of the GFP did not interfere with the functioning of the full-length or N-terminally deleted LDAgs when interacting with HBsAg for secretion; (iii) non-isoprenylated mutants [GFP-LDM and GFP-LD(31-214)M] could not co-secreted with HBsAg; (iv) the SDAg of HDV together with the GFP-LD, but not the GFP-LD(31-214), could be co-secreted by HBsAg; (v) the GFP-LD, but not the GFP-LD(31-214), exerted a dominant-negative role on HDV genome replication; and (vi) the sequential appearance of GFP-LD in the nucleoplasm, then the nucleolus and finally in nuclear speckles (NS). Isoprenylation of LDAg seems to be important for targeting to and accumulating in the NS, which was evident from the dynamic and static localization of the non-isoprenylation mutant (GFP-LDM) and the distribution of wild-type (GFP-LD) when treated with an isoprenylation inhibitor, lovastatin, for more than 48 hr. Permanently expressing GFP-LD cells studies showed that dephosphorylated GFP-LD translocated from the nucleolus to the SC-35 containing NS in the presence of dichlororibofuranosyl benzimidazole (DRB) and then back to the nucleolus within 2 hr after removing of DRB or staurosporine. When GFP-LD cells treated with okadaic acid the GFP-LD accumulated in nucleolus only.
In the study of the role of M-HBsAg in HDV antigen packaging and secretion, The results indicated that the M-HBsAg could pack LDAg, or together with SDAg, but not HDV ribonucleoprotein (RNP) complex. The inability of packaging HDV RNP by M-HBsAg may open an avenue for studing how the HDV RNP and LDAg interact with HbsAg in the future.

封面
中文摘要
英文摘要
緒論
材料與方法
結果
討論
參考文獻

參考文獻
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