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系統識別號 U0026-2007201011363200
論文名稱(中文) 自噬作用促使丙型干擾素誘發Jak2-STAT1活化及細胞發炎反應
論文名稱(英文) Autophagy Facilitates IFN-gamma-induced Jak2-STAT1 Activation and Cellular Inflammation
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 98
學期 2
出版年 99
研究生(中文) 張鈺苹
研究生(英文) Yu-Ping Chang
電子信箱 s4697104@mail.ncku.edu.tw
學號 s4697104
學位類別 碩士
語文別 英文
論文頁數 80頁
口試委員 指導教授-林秋烽
口試委員-林以行
口試委員-劉校生
口試委員-黃偉邦
中文關鍵字 自噬作用  丙型干擾素  Jak2  STAT1  SHP2  ROS  發炎 
英文關鍵字 Autophagy  IFN-γ  Jak2  STAT1  SHP2  ROS  Inflammation 
學科別分類
中文摘要 自噬作用 (autophagy) 是一種藉由自噬小體 (autophagosome) 將細胞內異常堆積的蛋白質或是細胞內老化或受損的胞器 (如粒線體) 進行包裹作用。自噬小體與溶酶體融合形成自噬溶酶體 (autophagolysosome) 並利用溶酶體內的酵素將包裹物清除以維持細胞存活及代謝平衡。近幾年的報導指出自噬作用參與在細胞對抗結核菌的感染過程中,被認為是一種細胞抵禦外來感染的機制。除此之外,丙型干擾素 (IFN-γ) 誘導的Irgs (IFN-inducible immunity-related GTPases) 蛋白能引發自噬作用的發生,然而其詳細的分子機制並不清楚。本研究中,我們證明自噬作用能促進丙型干擾素的訊號傳遞係以透過調控Jak2-STAT1進而影響細胞的發炎反應。在Atg5基因剔除 (Atg5-/-) 的小鼠胚胎纖維母細胞中,丙型干擾素刺激無法誘發自噬作用的產生;同時,丙型干擾素下游基因-干擾素調節因子1 (IRF-1) 的表現量也顯著的較為低下。利用第三型 PI3K (class III phosphatidylinositol 3-kinase) 的抑制劑3-MA (3-methyladenine) 抑制自噬作用的產生,也可以發現不管在小鼠胚胎纖維母細胞或是RAW264.7巨噬細胞皆可以抑制丙型干擾素誘發的自噬現象以及細胞發炎反應。在另一個Atg7基因剔除 (Atg7-/-) 的小鼠胚胎纖維母細胞也可以觀察到與Atg5-/-小鼠胚胎纖維母細胞有著同樣的效果,諸如無法形成自噬作用、較低的細胞發炎反應抑或是Jak2-STAT1活化受到抑制。在丙型干擾素訊息傳遞過程,負向調控因子包括SOCS1 (suppressor of cytokine signaling-1)、SOCS3和SHP2 (dual-phosphatase Src homology-2 domain-containing phosphatase) 參與其中的調控。透過shRNA (lentiviral-based short hairpin RNA) 抑制了SHP2的表現可增加丙型干擾素誘導的STAT1磷酸化表現量,顯示在Atg5-/-的細胞中SHP2扮演抑制丙型干擾素訊息傳遞的角色。此外,在缺乏自噬作用的細胞中,ROS (reactive oxygen species) 的表現和粒線體的含量都較高,並能活化SHP2進而抑制丙型干擾素的訊息傳遞及細胞發炎反應。綜合以上實驗結果,自噬作用能透過調控Jak2-STAT1的活性促進丙型干擾素的訊號傳遞,進而影響細胞的發炎反應。
英文摘要 Autophagy is a mechanism for degrading aggregated proteins and damaged organelles such as mitochondria, which has important roles in development, immune defense, programmed cell death, and neurodegeneration. Recent report showed that autophagy is a defense mechanism, which participated in host cell resistance to Mycobacterium. One way that autophagy participates in regulation of immunity is it enhances interferon (IFN)-γ-mediated antimicrobial efficacy; however, the effects of autophagy on IFN-γ signaling and bioactivaties remain unclear. In this study, we investigate that autophagy facilitates IFN-γ signal activation by regulating Janus kinase (Jak) 2 and signal transducer and activator of transcription (STAT) 1 signal and influencing cellular inflammation. Autophagy protein (Atg) 5 deficient (Atg5-/-) mouse embryonic fibroblasts (MEFs) are resistant to IFN-γ-induced light chain 3 (LC3) conversion as well as autophagosome formation. At the same time, IFN-γ-induced IFN regulatory factor 1 expression was significantly lower. We used 3-MA (3-methyladenine) which is a PI3K (class III phosphatidylinositol 3-kinase) inhibitor, inhibiting autophagy formation. Either MEFs or RAW264.7, which is macrophage like cell, inhibited IFN-γ-induced autophagy and cellular inflammation. Both of Atg5-/- and Atg7-/- MEFs are resistant to IFN-γ-activated Jak2-STAT1, which suggests autophagy has a potent role in IFN-γsignaling. There are negative regulator such as SOCS1 (suppressor of cytokine signaling-1), SOCS3, and SHP2 (dual-phosphatase Src homology-2 domain-containing phosphatase) in IFN-γ signal pathway. Inhibited SHP2 expression increase IFN-γ-induced STAT1 phosphorylation by shRNA (lentiviral-based short hairpin RNA), SHP2 play the inhibition role of IFN-γ signaling in Atg5-/- MEFs. In addition, increased reactive oxygen species (ROS) result from the absence of autophagy positively regulates SHP2, which inactivates STAT1. Image analysis shows that IFN-γ promotes co-localization of autophagosomes and ROS-producing mitochondria, which lead to the clearance of aged mitochondria. Atg5-/- MEFs fail to generate autophagy result in abundant ROS produced mitochondria exist. This study reveals a link between autophagy and IFN-γ signaling and bioactivities, and autophagy plays a pivotal role of Jak2-STAT1 through inhibition of ROS and SHP2 and influencing on cellular inflammation.
論文目次 Abstract in Chinese......................... 1
Abstract in English ......................... 3
Acknowledgement......................... 5
Contents............................... 6
Abbreviations ............................ 10
Chapter I Introduction............................. 14
I-1. The original finding of autophagy .......................14
I-2. The formation and its component of autophagosome..............14
I-2-1. ATG5...................................15
I-2-2. ATG8...................................16
I-3. The physiological role of autophagy......................16
I-3-1. Cell survival and cell death 16
I-3-2. Development 17
I-3-3. Autophagy participate in immunity 18
I-4. IFN-γ.......................................20
I-4-1. Activation of IFN-γ and signaling.....................20
I-4-2. Biofunction of IFN-γ ............................21
I-5. IFN-γ-induced autophagy.............................22
Chapter II Hypothesis ............................. 23
Specific Aims ........................... 23
Chapter III Materials and Methods....................... 25
III-1. Cells and media ................................25
III-2. Luciferase activity assay............................25
III-3. Enzyme-linked immunosorbent assay (ELISA)................26
III-4. Western blot ...................................26
III-5. Autophagy assay.................................27
III-6. Cell imaging..................................27
III-7. Lentiviral-based shRNA transfection. .....................27
III-8. Cell proliferation................................27
III-9. Plaque assay..................................28
III-10. Detecting ROS ................................28
III-11. Co-immunoprecipitation ...........................28
III-12. Immunostaining followed by flow cytometry ................28
III-13. Mitochondria DNA assay ..........................29
III-14. Statistical analysis ..............................29
Chapter IV Results................................ 30
IV-1. IFN-γ induces autophagy in MEFs......................30
IV-2. Autophagy is critical for IFN-γ-induced bioactivity..............30
IV-3. Autophagy is critical for IFN-γ-induced anti-cell proliferation and inhibition of viral replication ..........................31
IV-4. Autophagy inhibition reduces IFN-γ-induced inflammation........31
IV-5. Effects of autophagy on the expression of IFN-γ receptors and the activation of Jak2 signaling...........................32
IV-6. Autophagy is important for IFN-γ-activated STAT1............32
IV-7. Generation of ROS is deregulated in the absence of autophagy and negatively regulates IFN-γ-induced STAT1 activation ...........33
IV-8. SHP2 inhibits IFN-γ-activated STAT1 in the absence of autophagy .....35
IV-9. Autophagic stimuli and suppression of SHP2 facilitates IFN-γ-induced STAT1 activation in K562 cells .........................36
IV-10. Autophagic stimuli enhance IFN-γ-induced STAT1 activation ......37
Chapter V Conclusion ............................. 38
Chapter VI Discussion .............................. 39
Chapter VII References.............................. 42
Chapter VIII Figure and Figure Legends .................... 50
Figure 1. IFN-γ induces autophagy.........................50
Figure 2. Autophagy is critical for IFN-γ-induced inflammation..........51
Figure 3. Autophagy is critical for IFN-γ-induced anti-proliferation and inhibition of viral replication. .........................52
Figure 4. Autophagy inhibition reduces IFN-γ-induced inflammation.......53
Figure 5. Effects of autophagy on the expression of IFN-γ receptors and Jak2 association with IFNGR2. ........................54
Figure 6. STAT1 phosphorylation and downstream IRF1 and SOCS1 expression are decreased in the absence of autophagy ...........55
Figure 7. STAT1 expression is decreased in the absence of autophagy.......56
Figure 8. Autophagy is required for IFN-γ-induced Jak2-STAT1 phosphorylation and cellular inflammation. .................57
Figure 9. Generation of ROS in mitochondria and absence of autophagy results in the high level of ROS and mitochondria. ..............58
Figure 10. SHP2 inhibits IFN-γ-activated STAT1 in the absence of autophagy....................................60
Figure 11. SHP2 mediates the inhibition of IFN-γ-induced nitrite generation in the absence of autophagy. .........................61
Figure12. Autophagic stimuli and suppression of SHP2 facilitate IFN-γ-induced STAT1 activation in K562 cells. ................62
Figure13. Autophagic stimuli facilitates IFN--induced STAT1 activation....63
Figure14. Model of autophagy facilitates IFN-γ-induced Jak2-STAT1 activation.....................................64
Appendix.............................. 65
A. Materials............................. 65
A-1 Chemicals.....................................65
A-2 Antibodies ....................................67
A-3 ELISA Kit....................................67
A-4 Kits .........................................68
A-5 Dyes ........................................68
A-6 Consumables ...................................68
A-7 Apparatus ....................................68
B. Methods............................. 69
B-1 Cell culture ....................................69
B-1.1 Cell culture medium ............................69
B-1.2 Cell passage.................................70
B-1.3 Cell freeze .................................70
B-1.4 Cell defreeze ...............................71
B-2 Western blot...................................71
B-2.1 Lysis buffer .................................71
B-2.2 5× loading dye and TBS-T.........................71
B-2.3 Running gel preparation .........................72
B-2.4 Stacking gel preparation..........................72
B-2.5 Cell lysate preparation ..........................72
B-2.6 SDS-PAGE................................73
B-3 Enzyme-linked immunosorbent assay (ELISA).................73
B-4 Immunocytofluorescent..............................74
B-5 PCR ........................................74
B-5.1 DNA preparation..............................74
B-5.2 PCR program ...............................75
B-6 Lentiviral-based shRNA knockdown ......................76
B-6.1 Plasmid preparation ............................76
B-6.2 Lentiviral production...........................76
B-6.3 Lentiviral concentration..........................78
B-6.4 Lentiviral infection.............................78
CURRICULUM VITAE..................... 79
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