白點症(white spot disease, WSD)是由白點症病毒(white spot syndrome virus, WSSV)所引起的嚴重傳染性水產動物疾病，可於感染後一週內達到100%的致死率。WSSV在感染宿主後會誘導瓦式效應產生能量並促進麩醯胺酸分解、脂肪生成和核酸合成的進行，以此為病毒複製提供前驅物及能量。其中核苷酸代謝對於病毒和癌細胞傳播遺傳訊息和促進疾病進展都至關重要。目前在白點症病毒之基因組中共有532 個 ORF被辨認出，儘管大多數的病毒蛋白與已知蛋白質沒有同源性。然而仍有WSSV基因可轉譯出與核酸合成相關酵素的同源性蛋白。因此本研究著重於下列WSSV基因：WSSV228、WSSV243、WSSV168、WSSV124、WSSV454，這些基因分別可轉譯出: 核糖核苷酸還原酶1 (Ribonucleotide reductase large subunit, wRR1)、核糖核苷酸還原酶2 (Ribonucleotide reductase small subunit, wRR2)、脫氧尿酸三磷酸酶(deoxyuridine triphosphatase, wdUTPase)、胸苷酸合成酶 (Thymidylate synthase, wTS)、胸苷激酶和胸苷酸激酶（Thymidine kinase and thymidylate kinase, wTK-TMK），其中wTK-TMK為嵌合蛋白，對宿主蛋白TK及TMK同時表現出同源性。 這些WSSV基因皆參與在嘧啶新生中，透過消耗尿苷二磷酸 (UDP) 產生脫氧胸苷二磷酸 (dTDP)。 當在蝦體內注射對應的 dsRNA 並以 WSSV 感染時，會使WSSV早期及晚期基因表現下降，並使WSSV基因組複製數顯著下降。 因此我們推測這些病毒蛋白在病毒基因組複製階段 （WSSV注射後12小時）對於WSSV的致病機制很重要。為了了解這些WSSV基因與其他WSSV基因或宿主基因之間的關聯性，我們透過 Sf9 昆蟲細胞表現 wRR1 和 wTK-TMK重組蛋白，接著利用親和性純化質譜分析 (Affinity Purification-Mass Spectrometry, AP-MS)，分別篩選出可能與wRR1有交互作用的370個宿主蛋白及10個WSSV病毒蛋白；以及可能與wTK-TMK有交互作用的556個宿主蛋白及13個WSSV病毒蛋白，接著透過使用ContigViews以及實驗室先前所建立之轉錄梯學資料庫構建蛋白質-基因關聯網路，並從這些蛋白中選出位於負相關中心之XP_027212313 (uncharacterized protein)以及參與glycolysis中但尚未在WSSV研究中被深入探討的果糖-1,6-二磷酸醛縮酶 (Fructose-1,6-bisphosphate aldolase, LvFBA)和葡萄糖-6-磷酸異構酶 (Glucose-6-phosphate isomerase, LvGPI) 作為潛在宿主蛋白，這些蛋白在蝦類 WSSV 致病機制中可能至關重要， 當在蝦體內注射 LvGPI之dsRNA並以WSSV感染後，會使WSSV早期及晚期代表性基因表現下降，並使WSSV基因組複製數顯著下降。因此我們推測LvGPI在WSSV複製其間扮演重要的角色。同時，為了瞭解wTK-TMK與其他WSSV病毒蛋白是否有直接地相互作用，我們透過酵母菌雙雜合系統 (Yeast-two-hybrid)篩選與wTK-TMK有潛在交互作用能力的WSSV蛋白。總之研究結果表示病毒蛋白wRR1, wRR2, wTS, wTK-TMK以及宿主蛋白LvGPI對在WSSV 病毒複製過程中扮演重要的角色，並透過親和性純化質譜分析及酵母菌雙雜合系統篩選出與wRR1或wTK-TMK有潛在結合能力的蛋白，以供進一步的探討。

White Spot Disease (WSD), a severe disease in crustaceans, is caused by White Spot Syndrome Virus (WSSV), which causes 100% mortality within 1 week after infection. To promote its replication, WSSV will trigger the Warburg effect and induce glutaminolysis, lipogenesis, and nucleic acid synthesis to provide energy and bioproduct for viral replication. In particular, nucleotide metabolism is important for both virus and cancer cells to disseminate genetic information and promote disease progression. In total, 532 ORFs have been identified in the WSSV genome, although most of them have no similarity to known proteins. However, there are some WSSV proteins that show homology to enzymes involved nucleic acid metabolism. Our objective was to focus these WSSV proteins: ribonucleotide reductase 1 (wRR1), ribonucleotide reductase 2 (wRR2), dUTP diphosphatase (wdUTPase), thymidylate synthase (wTS), thymidine kinase and thymidylate kinase (wTK-TMK). These proteins are involved in de novo pyrimidine synthesis to produce deoxythymidine diphosphate (dTDP) from uridine diphosphate (UDP). When shrimp were injected with corresponding dsRNA and challenged with WSSV, there were significant decreases in both WSSV gene expression and WSSV genome copies. Therefore, we speculated that these viral proteins are important for WSSV pathogenesis at the viral replication stage (12 h post WSSV injection), which can further influence WSSV gene expression and viral genome copies. To understand the association between these viral proteins with other WSSV viral proteins and host proteins, wRR1 and wTK-TMK were transfected into sf9 insect cells. By using affinity-purification mass spectrometry (AP-MS), we identified some cellular protein that might interact with wRR1 or wTK-TMK. In total, there are 370 host proteins and 10 WSSV proteins in wRR1 bound proteins, and there are 556 host proteins and 12 WSSV proteins in wTK-TMK bound proteins. In all of these proteins, XP_027212313, LvGPI and LvFBA were identified as potential host genes that may be critical during WSSV pathogenesis in shrimp. Also, yeast-two-hybrid system was used to screen WSSV proteins that might interact with wTK-TMK. The interaction need to be validated by co-immunoprecipitation. In conclusion, this study revealed the importance of wRR1, wRR2, wTS, wTK-TMK and LvGPI during WSSV replication in shrimp, and identified potential proteins that might interact with wRR1 or wTK-TMK to regulate pyrimidine biosynthesis.

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陳有健，白蝦SIRT4在白點症所誘導之代謝變化及病毒複製的參與，國立成功大學生物科技與產業科學系碩士論文，2022。
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