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系統識別號 U0026-2608201312525000
論文名稱(中文) 登革病毒需要透過誘發內質網壓力活化自噬反應以及促進病毒複製
論文名稱(英文) Dengue virus-induced ER stress is required for autophagy activation and viral replication
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 101
學期 2
出版年 102
研究生(中文) 郭思含
研究生(英文) Szu-Han Kuo
學號 S46004022
學位類別 碩士
語文別 英文
論文頁數 67頁
口試委員 指導教授-劉校生
口試委員-林以行
口試委員-王貞仁
口試委員-李英瑞
中文關鍵字 登革病毒  內質網壓力  未摺疊蛋白反應  自噬作用 
英文關鍵字 Dengue virus  ER stress  Unfolded protein response  Autophagy 
學科別分類
中文摘要 內質網是個與核膜相連的重要的胞器,負責蛋白質的合成與摺疊,同時也扮演著調控細胞內部離子恆定的角色。一旦內質網的恆定受到破壞時,就會產生內質網壓力(ER stress),若細胞持續處在ER stress下,最終會導致細胞凋亡(apoptosis)。生物體發展出unfolded protein response (UPR)的機制用以緩和ER stress以防止細胞死亡。UPR包括PERK、IRE1以及ATF6三條訊息傳遞路徑,目的都是要減少ER stress使細胞能繼續存活。先前研究指出,登革病毒(DV)感染不只會引起ER stress的產生,且會有順序性的調控三條UPR訊息傳遞路徑,最早活化的是PERK,接著是IRE1最後才是ATF6路徑,這種調控方式使得宿主細胞不會因病毒感染所造成的持續性ER stress而死亡。另一方面,ER stress除了會導致apoptosis,同時也會活化自噬作用(autophagy)幫助細胞的生存。Autophagy是維持細胞內能量恆定的重要機制,其特色是在作用發生時會產生一雙層膜構造的囊泡稱為自噬體(autophagosome)包裹細胞質內的物質,而後與溶體融合並把內涵物降解掉。實驗室先前研究已發現DV感染會誘發autophagy的產生而促進病毒的複製。然而DV感染時所誘發ER stress對於引起autophagy反應以及對病毒複製的影響目前仍待釐清。本研究之中假說為DV所引發的ER stress會透過UPR路徑活化autophagy,進而促進病毒在細胞內的複製。實驗結果顯示DV需要透過ER stress誘發autophagy而促進病毒複製,而且DV對於三條UPR路徑的調控順序在不同細胞株間都有相似情況。分別抑制三條UPR路徑後觀察到,只有PERK與IRE1訊息傳遞路徑會參與在ER stress誘發的autophagy機制以及影響DV的複製。第一條路徑PERK-eIF2α在病毒感染後6小時就會被活化,且eIF2α下游所調控的路徑之一ATF4-ATG12路徑參與在誘發autophagy的過程。第二條路徑為IRE1,此路徑有兩條分支:其一是IRE1α-XBP1,在病毒感染後24小時活化,然而此路徑也不參與在autophagy的誘發,也不影響病毒子代的產生;而另一條為IRE1α-JNK,此路徑在IRE1α活化時也被活化,觀察到IRE1α-JNK會參與autophagy的誘發機制,且會影響病毒的複製。再深入探討JNK的下游Bcl-2-BECN1路徑,發現在感染後36小時,被IRE1α活化的JNK會磷酸化其下游的Bcl-2。Bcl-2一旦被磷酸化就會與BECN1分離,而脫離Bcl-2的BECN1就能執行其誘發autophagy的功能。第三條訊息路徑是ATF6,連續時間點的實驗中發現,無論是肝癌細胞株(Huh7)或是肺癌細胞株(A549)在感染後36小時這個autophagy被DV誘發的時間點之前,未見ATF6路徑有被活化的現象,而且抑制ATF6表現也對autophagy活性和病毒複製沒有影響。以上結果顯示PERK-eIF2α-ATF4-ATG12以及IRE1α-JNK-BECN1訊息傳遞路徑參與在DV所誘發的autophagy現象而促進病毒的複製。進一步研究發現抑制XBP1的表現,會使IL-8以及TNFα這兩個在DV感染時被大量表現的發炎細胞激素的mRNA 表現有被抑制的現象。總結以上,本研究發現由DV感染引起的ER stress參與在活化autophagy的路徑而影響病毒子代的複製,另一方面我們也發現DV誘發的ER stress會調控發炎因子的產生,而這現象可能會參與在DV重症DHF與DSS的形成機轉。
英文摘要 Dengue virus (DV) replication associates with the endoplasmic reticulum (ER) where the virus assembles and buds into the lumen. The unfolded protein response (UPR) is a cellular ER stress response triggered by accumulation of unfolded proteins in the ER lumen. It has been reported that DV infection temporally modulates three branches of UPR, the first activated is PERK pathway, followed by IRE1 and the last is ATF6 signaling pathway. ER stress can also induce autophagy, a process wherein the cytoplasmic materials are packaged in the double membrane vesicles designated as autophagosome and degraded after fusing with lysosomes. We and others have reported that DV infection induces autophagy which further promotes DV replication. However, the role of ER stress in DV-induced autophagy and effect on viral replication remain unclear. We hypothesized that DV-induced ER stress activates autophagy and promotes viral replication through UPR. Our data showed that ER stress is indispensable for DV-induced autophagy and the modulation of UPR is a general event in various infected cell lines. We also demonstrated that PERK and IRE1 signaling pathways were involved in ER stress-induced autophagy and DV replication. Further study showed that PERK-eIF2α signaling pathway was induced at 6 h post infection (p.i.). Moreover, the eIF2α-regulated ATF4-ATG12 signaling pathway affected autophagy induction. The IRE1α-XBP1 signaling pathway was activated at 24 h p.i. and showed no effect on autophagy activity and DV production. However, IRE1α-XBP1 signaling pathway participated in the production of inflammatory cytokines including IL-8 and TNFα. Differently, IRE1α-JNK signaling pathway was activated and required for autophagy activation and DV replication. Further analysis showed that IRE1α-JNK downstream molecule Bcl-2 was phosphorylated by activated JNK and dissociated from BECN1, which participated in autophagy induction. The third pathway ATF6 was induced at 48 h p.i. and showed no effect on autophagy activity and DV production compared to the other two pathways. In summary, PERK-eIF2α-ATF4-ATG12 and IRE1α-JNK-BECN1 signaling pathways were required for DV-induced autophagy and the promotion of DV replication. Altogether, we reveal that DV2-induced ER stress plays a pivotal role in autophagy induction, DV replication as well as inflammatory cytokine production.
論文目次 Abstract in Chinese I
Abstract in English III
Acknowledgements V
Contents VI
Abbreviation VIII
Introduction 1
Materials and Methods 7
Cell culture and dengue virus 7
Plaque assay 7
Western blotting 8
Immunoprecipitation (IP) 9
Transient transfection 9
PCR 10
Immunofluorescent assay (IFA) 10
Animal experiment 11
Statistical analysis 12
Results 13
DV2-induced ER stress is at up-stream of autophagy and affects viral replication
13
Induction of UPR by DV2 infection is a general event in various infected cell lines 14
PERK and IRE1 signaling pathways are involved in DV2-induced autophagy 15
PERK-eIF2α-ATF4-ATG12 pathway participates in autophagy induction during DV2 infection 16
IRE1α-XBP1pathway is indispensable in DV2-induced autophagy and viral replication 16
IRE1α-JNK-BECN1 signaling pathway participates in DV2-induced autophagy and viral replication 18
DV2 infects the brain of the ICR suckling mice and induces both ER stress and autophagy 19
JNK inhibitor SP600125 inhibits autophagy and decreases the disease symptoms of DV2 infected suckling mice 20
Discussion 22
References 28
Figures 40
Appendix 64
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