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系統識別號 U0026-1212201622535300
論文名稱(中文) 干擾素γ引起之自噬作用受S100A10調控並且是annexin A2 exophagy必要的過程
論文名稱(英文) IFN-γ-induced autophagy is regulated by S100A10 and required for exophagy of annexin A2
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 105
學期 1
出版年 105
研究生(中文) 陳盈達
研究生(英文) Ying-Da Chen
學號 S58991316
學位類別 博士
語文別 英文
論文頁數 111頁
口試委員 指導教授-林以行
召集委員-張志鵬
口試委員-劉校生
口試委員-蔣輯武
口試委員-林秋烽
口試委員-張堯
中文關鍵字 自噬體的形成  干擾素γ  S100A10  ULK1 的轉移  HMGB1  Annexin A2  多泡體  RAB 蛋白  Exophagy 
英文關鍵字 Autophagosome formation  Interferon-γ  S100A10  ULK1 translocation  HMGB1  Annexin A2  MVB  RAB proteins  Exophagy 
學科別分類
中文摘要 自噬作用相關蛋白(ATG proteins)會在自噬作用(autophagy)過程中轉移到自噬體(autophagosome)形成的位置。我們在本研究證明了,S100A10對於ULK1轉移到自噬體形成的位置是必須的。抑制S100A10基因表現可以降低自噬體的形成。我們也偵測S100A10的結合蛋白annexin A2 (ANXA2)的角色,ANXA2已經被報導可以促進吞噬泡(phagophore)的聚集。抑制ANXA2基因表現可以降低S100A10蛋白。然而,在ANXA2基因表現被抑制的細胞中過度表現S100A10仍然可以增強自噬體的形成,這表示ANXA2是透過S100A10來調控干擾素γ引起的自噬作用。我們也觀察到,在干擾素γ刺激下S100A10會和ULK1交互作用,而且抑制S100A10基因表現可阻止ULK1轉移到自噬體形成的位置。HMGB1的釋放在抑制S100A10基因表現的細胞中是被限制的。這些結果釐清了S100A10在自噬體形成時的重要性,並且揭露干擾素γ引起之自噬作用中S100A10和ULK1的關係。我們先前證明了干擾素γ引發的ANXA2分泌,和外泌體(exosome)釋放相關。此外,S100A10對於干擾素γ引起之ANXA2非典型外泌體分泌是必須的。所以我們研究干擾素γ引發之自噬作用在ANXA2外泌體分泌中可能的角色。在此,我們發現在肺上皮細胞中,干擾素γ引發之自噬作用對於ANXA2分泌到細胞外是必要的。我們觀察到在干擾素γ的刺激之後,含有ANXA2的自噬體會和多泡體(multivesicular bodies, MVBs)疊合並利用外泌體分泌ANXA2。在抑制ATG5基因表現的細胞或是RAB11突變的細胞中,我們看不到干擾素γ引起的ANXA2 exophagy。此外, 抑制RAB8A和RAB27A基因表現可降低干擾素引起的ANXA2分泌,但是抑制RAB27B基因表現卻不行。轉移到細胞表面的ANXA2可增強上皮細胞的胞葬作用(efferocytosis),而抑制exophagy則可以降低ANXA2媒介的胞葬作用,exophagy的過程包括自噬體的形成、自噬體和多泡體融合、自噬內涵體(amphisomes,自噬體和多泡體融合形成的囊泡)和細胞膜融合。我們的結果揭露了S100A10調控干擾素引發自噬作用的方式,以及ANXA2 exophagy的路徑。結合這兩項發現可以推測,在干擾素刺激之後S100A10會和ULK1交互作用並促使自噬體形成,之後ANXA2被包裹進自噬體。含有ANXA2的自噬體和多泡體融合,並進一步和細胞膜融合來釋放含有ANXA2的外泌體。所以,ANXA2可藉此轉移到細胞表面來增強細胞的胞葬作用(efferocytosis)。胞葬作用對於避免產生自體免疫或不正常發炎反應很重要。此外,HMGB1也和慢性發炎的調節有關。因此,我們的結果暗示著S100A10媒介的自噬作用以及ANXA2 exophagy有助於免疫系統的平衡。
英文摘要 During the process of autophagy, the autophagy-related (ATG) proteins are translocated to autophagosome formation sites. In this study, we demonstrate that S100A10 is required for ULK1 localization to autophagosome formation sites. Silencing of S100A10 reduces IFN-γ-induced autophagosome formation. We also determined the role of annexin A2 (ANXA2), a binding protein of S100A10, which has been reported to promote phagophore assembly. Silencing of ANXA2 reduced S100A10 expression. However, overexpression of S100A10 in ANXA2-silenced cells was still able to enhance autophagosome formation, suggesting that ANXA2 regulates IFN-γ-induced autophagy through S100A10. We also observed that S100A10 interacted with ULK1 after IFN-γ stimulation, and S100A10 knockdown prevented ULK1 localization to autophagosome formation sites. The release of HMGB1 was inhibited in S100A10 knockdown cells. These results elucidate the importance of S100A10 in autophagosome formation and reveal the relationship between S100A10 and ULK1 in IFN-γ-induced autophagy. We previously demonstrated that IFN-γ-triggered ANXA2 secretion is associated with exosomal release. Furthermore, S100A10 is required for IFN-γ-induced unconventional exosome secretion of ANXA2. Therefore, we investigated the potential roles of IFN-γ-induced autophagic pathway in exosomal secretion of ANXA2. Here, we show that IFN-γ-induced autophagy is essential for the extracellular secretion of ANXA2 in lung epithelial cells. We observed colocalization of ANXA2-containing autophagosomes with multivesicular bodies (MVBs) after IFN-γ stimulation, followed by exosomal release. IFN-γ-induced exophagic release of ANXA2 could not be observed in ATG5-silenced or mutant RAB11-expressing cells. Furthermore, knockdown of RAB8A and RAB27A, but not RAB27B, reduced IFN-γ-triggered ANXA2 secretion. Surface translocation of ANXA2 enhanced efferocytosis by epithelial cells, and inhibition of different exophagic steps, including autophagosome formation, fusion of autophagosomes with MVBs, and fusion of amphisomes with plasma membrane, reduced ANXA2-mediated efferocytosis. Our data reveal the regulation of S100A10 in IFN-γ-induced autophagy and a novel route of IFN-γ-induced exophagy of ANXA2. Connecting the two findings, IFN-γ-induced S100A10 interacts with ULK1 to trigger autophagosome formation and then ANXA2 is engulfed by autophagosome. ANXA2-containing autophagosome fuses with MVB and further fuses with the plasma membrane to release ANXA2-containing exosomes. Therefore, ANXA2 translocates to cell surface to enhance efferocytosis. Efferocytosis is important in prevention of autoimmune and inflammatory disorders. Furthermore, HMGB1 is associated with the regulation of chronic inflammation. Therefore, our results indicate that S100A10-mediated autophagy as well as exophagy of ANXA2 may contribute to immune system balance.
論文目次 English Abstract I
中文摘要 III
誌謝 V
Contents VI
Figure List X
Abbreviations XIII
Chapter 1 Introduction 1
1.1 IFN-γ 1
1.1.1 IFN-γ in immunity 1
1.1.2 IFN-γ signaling pathway 2
1.2 Autophagy 2
1.2.1 Autophagy process 3
1.2.2 Induction signals of autophagy 4
1.2.3 Exophagy 4
1.2.4 RAB proteins and autophagy 6
1.3 S100A10 and annexin A2 7
1.3.1 Functions of S100A10 and annexin A2 8
1.3.2 Secretion of annexin A2 8
1.3.3 S100 proteins and autophagy 9
1.4 S100A10 and ANXA2 studies in our lab 9
Chapter 2 Specific Aims 11
Chapter 3 Materials and Methods 13
3.1 Materials 13
3.1.1 Cell lines 13
3.1.2 Drugs 13
3.1.3 Kits 14
3.1.4 Antibodies 15
3.1.5 Vectors 16
3.1.6 Primer 17
3.1.7 Consumables 18
3.1.8 Instruments 18
3.2 Methods 18
3.2.1 Cell cultures 18
3.2.2 Cell treatment and HMGB1 secretion assay 19
3.2.3 Immunoprecipitation and western blotting 19
3.2.4 Reverse transcription polymerase chain reaction (RT-PCR) and RT-qPCR 20
3.2.5 Immunofluorescence microscopy 20
3.2.6 Transmission electron microscopy 21
3.2.7 shRNA and Myc-ULK1 overexpression 21
3.2.8 Plasmid transfection 22
3.2.9 Exosome isolation 22
3.2.10 Phagocytosis assay 23
3.2.11 Statistical analysis 23
Chapter 4 Results 24
4.1 To investigate the role of S100A10 in IFN-γ-induced autophagy 24
4.1.1 S100A10 is essential for IFN-γ-induced autophagy in human lung epithelial cells 24
4.1.2 S100A10 overexpression triggers autophagosome formation in ANXA2 knockdown cells 25
4.1.3 S100A10 triggers IFN-γ-induced autophagosome formation through ULK1 26
4.1.4 HMGB1 release is inhibited in S100A10 knockdown cells 28
4.2 To investigated the potential roles of autophagic pathway in exosomal secretion of ANXA2 29
4.2.1 IFN-γ-induced autophagy is essential for extracellular secretion of ANXA2 in lung epithelial cells 29
4.2.2 IFN-γ-induced autophagy regulates exosomal secretion of ANXA2 30
4.2.3 RAB11 is required for exophagy of ANXA2 30
4.2.4 Amphisome/lysosome fusion is not required for ANXA2 exosomal secretion 31
4.2.5 RAB8A and RAB27A regulate ANXA2 secretion 32
4.2.6 Inhibition of exophagy reduces ANXA2-mediated efferocytosis 33
Chapter 5 Discussion 34
5.1 The interaction between ANXA2 and S100 proteins in autophagosome formation 34
5.2 The role of S100A10 in induction signals of autophagy 35
5.3 S100A10 and ATG proteins 36
5.4 S100A10 and HMGB1release 36
5.5 S100A10 and autophagy-mediated physiological processes 38
5.6 ANXA2 secretion and autophagy 39
5.7 ANXA2 and autophagosome 40
5.8 ANXA2 and amphisomes 41
5.9 ANXA2 and lysosome-dependent protein secretion 42
5.10 ANXA2 and RAB proteins 43
5.11 IFN-γ-induced autophagy 43
Chapter 6 Conclusions 45
References 47
Figures and Figure legends 63
Appendix 105
Curriculum Vitae 109
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