Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/97562
標題: 家禽里奧病毒p17及σA蛋白調控autophagy、proteasome、glycolysis及TCA cycle以利於病毒複製
Regulation of autophagy, proteasome, glycolysis and TCA cycle by avian reovirus p17 and σA proteins benefiting virus replication
作者: 紀佩宜
Pei-I Chi
關鍵字: 家禽里奧病毒;自體吞噬作用;蛋白酶體;三羧酸循環;三磷酸腺苷;Avian reovirus;ARV;autophagy;proteasome;ATP;TCA cycle;glutaminolysis;HIF-1α;mTORC1;LC3-II
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摘要: 
家禽里奧病毒(ARV)為里奧病毒科(Reoviridae family)之雙股RNA病毒,禽類感染可造成家禽病毒性關節炎、慢性呼吸道疾病及吸收不良症後群,導致業者之經濟損失。在我過去研究已證實家禽里奧病毒非結構性蛋白p17誘發自體吞噬作用有利於病毒複製,但其作用之機制仍不清楚。本研究證實不論感染家禽里奧病毒或直接轉染家禽里奧病毒p17基因,皆可正調控宿主細胞phosphatase and tensin homolog (PTEN) 及AMP-activated protein kinase (AMPK),進而降低mammalian target of rapamycin (mTOR)活性及增加微管相關蛋白輕鍵3-II (LC3-II) 之形成,誘發自體吞噬作用。另外,家禽里奧病毒非結構性蛋白p17亦調控PKR/eIF2α訊息傳遞途徑以促進自體吞噬作用。以shRNAs抑制LAMP2 及 Rab7a 之表現造成自體吞噬小體無法與細胞溶酶體結合,抑制病毒之複製。因此家禽里奧病毒非結構性蛋白p17促進 autophagosome 及 autolysosome 形成有利於病毒複製。
蛋白酶體為細胞主要降解蛋白質之機制之一,在細胞週期、凋亡與免疫系統皆扮演重要之角色。本實驗室過去研究發現以MG 132抑制proteasome活性,顯著減少家禽里奧病毒之複製。但作用之機制仍不清楚。本研究首次證實在感染家禽里奧病毒早期即可提升蛋白酶體結構蛋白proteasome subunit 6 (PSMB6)之表現及提升蛋白酶體之活性。抑制PSMB6之表現,顯著降低病毒力價。本研究證實家禽里奧病毒σA蛋白為主要調控此機制之病毒蛋白。σA促進PSMB6之表現進而促使rpl26及rpl27a被降解,進而抑制 mTORC2-ribosone 複合體形成,進一步抑制下游Akt及導致Beclin 1與14-3-3之結合量下降,因此促進自體吞噬小體 LC3-II 之形成。綜合以上研究證實家禽里奧病毒p17蛋白協同σA蛋白調控mTORC2及下游Akt,促進自體吞噬作用,以利病毒複製。本研究闡明家禽里奧病毒p17及σA蛋白如何調控autophagosome and autolysosome之形成以利病毒複製。
早期研究發現家禽里奧病毒會影響宿主細胞代謝相關蛋白之表現量。本研究首次證實σA透過提升isocitrate dehydrogenase [NAD] subunit beta (IDH3B)表現、glutaminolysis及活化HIF-1α 表現,進而正調控糖解作用之hexokinase、phosphofructokinase (PFK)、triose-phosphate isomerase (TPI) 及pyruvate kinase之mRNA表現。另一方面σA亦藉由抑制重要酵素lactate dehydrogenase A (LDHA)之表現,促進三羧酸循環及細胞ATP之生成。本研究更進一步發現病毒mRNA 之5端與3端非轉譯區之保守序列 (conserved region)。將此保守序列刪除,可顯著降低病毒之生合成,證實ATP生成是病毒蛋白合成不可或缺之因子。縱合上述結果證實家禽里奧病毒藉由影響細胞內回收系統之自體吞噬、蛋白酶體與ATP生成,提供細胞內蛋白生合成所需之能量及環境,以利病毒本身之複製。

Avian reoviruses (ARVs) are dsRNA viruses and members of the Orthoreovirus genus. ARV causes viral arthritis, chronic respiratory disease, and malabsorption syndrome, leading to a considerable economic loss to the poultry industry. My Master's study has demonstrated that ARV triggers autophagy to facilitate its replication, and the nonstructural protein p17 plays an important role in this regulation. However, the detailed mechanism of how ARV activates autophagy remain unclear. In the present study, I have uncovered that p17 activates PTEN to negatively regulate Akt. Accompanied with activation of AMPK, p17 suppresses mammalian target of rapamycin complex 1 (mTORC1) to increase the formation of LC3-II. Together with the regulation of the PKR/eIF2α pathway, this work discovers that p17 activates three distinct pathways to trigger autophagy. Furthermore, I have found that disruption of autophagosome-lysosome fusion with shRNAs targeting LAMP2 or Rab7a led to an inhibition of viral protein synthesis and virus yield, suggesting that autolysosome formation is essential during virus life cycle. An earlier study by our laboratory has demonstrated that inhibition of proteasome with MG132 results in a reduction of virus yield. However, the underlying mechanism remains unknown. In this work, I have discovered that the structural protein σA of ARV upregulates PSMB6, a subunit of proteasome and proteasome activity, which in turn promotes degradation of both rpl26 and rpl27a, thereby inhibiting mTORC2-ribosome association. This further inhibits Akt and dissociates 14-3-3 and Beclin 1, leading to enhanced autophagosome formation. Additionally, the past and present studies revealed that p17 and σA cooperate to suppress mTORC2 and Akt for triggering autophagy, thus benefiting the virus replication. Collectively, these findings provide mechanistic insights into how the p17 and σA proteins of ARV induce autophagosome and autolysosome formation to benefit virus replication.
Moreover, we demonstrated that σA is involved in the regulation of cellular metabolism which is critical for virus replication. σA triggers IDH3B and glutaminolysis, which in turn activate HIF-1α to enhance several key enzymes in the glycolysis. Together with LDHA inhibition, σA enhances the TCA flux and increase the ATP formation, which is critical for viral protein synthesis. Besides, the conserved untranslated regions (UTRs) of 5'- and 3'-termini of the ARV genome segments have been identified, and deletion of these UTRs leads to a decrease in viral protein synthesis. Taken all together, this study reveals the mechanisms underlying ARV-modulated autophagy, proteasome activity and ATP formation to benefit virus replication.
URI: http://hdl.handle.net/11455/97562
Rights: 同意授權瀏覽/列印電子全文服務,2021-08-10起公開。
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