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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/62770完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 呂勝春 | |
| dc.contributor.author | Fu-Chia Yang | en |
| dc.contributor.author | 楊馥嘉 | zh_TW |
| dc.date.accessioned | 2021-06-16T16:09:55Z | - |
| dc.date.available | 2015-04-25 | |
| dc.date.copyright | 2013-04-25 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-03-18 | |
| dc.identifier.citation | REFERENCES
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/62770 | - |
| dc.description.abstract | SIK2是屬於AMPK家族的絲胺酸/蘇胺酸蛋白激酶(serine/threonine protein kinase)。過去的研究顯示，SIK2在脂肪細胞分化過程中具有調控早期胰島素訊息傳遞的功能，並可透過CREB調節反應賀爾蒙或營養狀態的基因表現。然而，SIK2活性的調控機制尚待研究釐清。在本研究中，我們發現當SIK2在第53位置的賴胺酸(Lys53)被p300/CBP乙醯化，會導致SIK2激酶活性受到抑制；而HDAC6可將SIK2的Lys53去乙醯化，並恢復其活性。此外，過量表現以麩醯胺酸取代Lys53(K53Q)的乙醯化擬態突變型(acetylation-mimetic mutant)，會造成SIK2聚集在自噬體(autophagosome)內；反之，以精胺酸取代Lys53(K53R)的抗乙醯化突變型(non-acetylatable mutant)則不會造成此現象。再者，我觀察到SIK2基因剔除(knockdown)會癱瘓自噬體和溶酶體的融合，更證實了SIK2及其活性為清除TDP-43Δ包涵體(inclusion body)所必需。值得注意的是在MG132處理的細胞中，內生(endogenous)SIK2聚集在自噬體內，且伴隨著SIK2乙醯化的上升；然而，同樣的現象並沒有發生在無血清培養的細胞中(serum-starved cells)。此結果說明蛋白酶體功能障礙(proteasome dysfunction)可能引發SIK2的乙醯化，並藉此清除隨之而生的蛋白質堆積。另一方面，我發現內質網蛋白質降解路徑的受質(ERAD substrate)由內質網到細胞質的逆向轉傳(retrotranslocation)，依然需要SIK2的激酶活性才能完成。不只SIK2，另一個SIK蛋白家族成員SIK3也同樣可被CBP和HDAC6所控制的乙醯化修飾。除了SIK家族的激酶，我更進一步地觀察到MARK1的活性如同SIK2一般，受控於由CBP和HDAC6所調節的乙醯化修飾。此現象暗示著MARK1在神經退化疾病中可能也受到類似的機制所調控。總結上述，本研究證明SIK2為調控內質網蛋白質降解路徑和自噬作用的關鍵因子，並可透過激酶與去乙醯酶(deacetylase)的交互作用共同調節細胞內蛋白質的平衡。 | zh_TW |
| dc.description.abstract | Salt-inducible kinase 2 (SIK2) is a serine/threonine protein kinase belonging to the AMP-activated protein kinase (AMPK) family. SIK2 has been shown to function in the insulin-signaling pathway during adipocyte differentiation and to modulate CREB-mediated gene expression in response to hormones and nutrients. However, molecular mechanism underlying the regulation of SIK2 kinase activity remains largely elusive. In this study, I report a dynamic, post-translational regulation of its kinase activity that is coordinated by an acetylation-deaceytlation switch – p300/CBP-mediated Lys53-acetylation inhibits SIK2 kinase activity, while HDAC6-mediated deacetylation restores the activity. Interestingly, overexpression of acetylation-mimetic mutant of SIK2 (SIK2-K53Q), but not the non-acetylatable K53R variant, resulted in sequestration of SIK2 in autophagosomes. Further consistent with a role in autophagy, knockdown of SIK2 abrogated autophagosome and lysosome fusion. Consequently, SIK2 and its kinase activity are indispensable for the removal of TDP-43Δ inclusion bodies. Remarkably, the accumulation of endogenous SIK2 in autophagosomes and the corresponding elevation of its acetylation were also observed in cells treated with MG132, yet not in serum-starved cells, revealing that this acetylation-based regulation may be induced by proteasome dysfunction and required for disposal of the resultant protein aggregates. Moreover, the requirement of SIK2 activity for retrotranslocation of ERAD substrate from ER to cytosol was evident. On the other hand, another SIK subfamily member, SIK3, was also modified reciprocally by CBP and HDAC6. In addition to SIK subfamily, the activity of MARK1 was under the control of CBP and HDAC6-mediated acetylation, implying its possible regulation in neurodegeneration diseases. Collectively, our findings uncover the critical roles of SIK2 in ERAD as well as autophagy progression and further suggest a mechanism in which the interplay among kinase and deacetylase activities coordinates cellular protein homeostasis. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T16:09:55Z (GMT). No. of bitstreams: 1 ntu-102-D96b46018-1.pdf: 6895370 bytes, checksum: e9cef250728ca3975ca909718ddfa68f (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | CONTENTS
口試委員會審定書 i 誌謝 ii 中文摘要 iii ABSTRACT iv Chapter 1. Literature Review 1 1.1 Protein homeostasis 1 1.1.1 ERAD and UPS 1 1.1.2 Autophagy 3 1.1.2.1 Overview of macroautophagy 4 Autophagosome formation 5 Autophagosome maturation 6 1.1.2.2 Deregulation of autophagy in diseases 8 Cancer 8 Inflammatory disorders 9 Neurodegeneration 9 1.2 Salt-inducible kinase 2 (SIK2) 10 1.2.1 SIK subfamily 10 1.2.2 The functions of SIK2 11 1.2.3 The regulations of SIK2 12 1.3 MAP/microtubule affinity regulating kinase 1 (MARK1) 13 1.3.1 The structure of MARK1 13 1.3.2 The functions of MARK1 15 1.3.3 The regulations of MARK1 15 1.4 Rationale 16 Chapter 2. Reversible Acetylation Regulates Salt-Inducible Kinase (SIK2) and Its Function in Autophagy 18 2.1 Introduction 18 2.2 Materials and methods 21 2.2.1 DNA constructs and mutagenesis 21 2.2.2 Antibodies 22 2.2.3 Cell culture and transfection 23 2.2.4 Immunoprecipitation and Western blot analysis 23 2.2.5 [γ-35S]ATP binding assay 24 2.2.6 Generation of 3D structure 24 2.2.7 CRE-reporter assay 25 2.2.8 Statistical analysis 25 2.2.9 Immunofluorescence staining and confocal microscopy 25 2.2.10 Electron microscopy 26 2.2.11 Preparation of soluble/insoluble fractions and slot blot analysis 27 2.2.12 Mass spectrometry analysis 27 2.2.13 In vitro deacetylation assay 28 2.2.14 In vitro kinase assay 28 2.3 Results 30 2.3.1 The ATP binding and kinase activity of SIK2 are impaired by K53-acetylation which is reciprocally regulated by p300/CBP and HDAC6 30 2.3.2 K53-acetylation-inactivated kinase activity of SIK2 is restored upon HDAC6-mediated deacetylation 32 2.3.3 Acetylation elicits SIK2 sequestration to autophagosomes 33 2.3.4 SIK2 is indispensible for the processing of autophagosomes 34 2.3.5 SIK2 activity is required for the clearance of TDP-43Δ inclusion bodies 35 2.3.6 Proteasome inhibition induces SIK2 acetylation and sequestration of SIK2 to autophagosomes 36 2.3.7 SIK3 and MARK1 are also under the control of CBP and HDAC6-mediated acetylation 38 2.4 Discussion 41 REFERENCES 47 FIGURES 66 Figure 1. Lys53 is 4 residues away from the critical residue for ATP-binding, Lys49 66 Figure 2. K53Q inhibits the ATP binding ability of SIK2 67 Figure 3. Structural alteration of SIK2 by K53-acetylation 68 Figure 4. The kinase activity of SIK2 K53Q is deficient 69 Figure 5. Kinase-deficient mutants recover SIK2-mediated inhibition of CRE activity 70 Figure 6. Inactivated SIK2 by CBP-mediated K53-acetylation is restored by HDAC6-mediated deacetylation 71 Figure 7. Kinase-deficient SIK2 is sequestrated in autophagosomes 72 Figure 8. Acetylation elicits SIK2 sequestration to autophagosomes 73 Figure 9. SIK2 is essential for autophagosome processing 74 Figure 10. SIK2 knockdown results in abnormal accumulation of multilamellar autophagosomes 75 Figure 11. SIK2 activity is required for the processing/removal of TDP-43Δ inclusion bodies 76 Figure 12. SIK2 is required for the retrotranslocation of ERAD substrate 78 Figure 13. SIK2-KD induces aggresome accumulation 80 Figure 14. Sequestration of endogenous SIK2 in autophagosome upon proteasome inhibition 81 Figure 15. SIK2 acetylation is elevated when proteasome function is blocked 82 Figure 16. MARK1 activity is also regulated by CBP and HDAC6-mediated acetylation 83 Figure 17. Lys37 is identified as an acetylation site on SIK3 by mass spectrometry 84 Figure 18. The acetylation on Lys41 of SIK3, the residue corresponding to SIK2-K53, is also regulated by CBP and HDAC6 85 Figure 19. Both Lys89 and Lys93 on MARK1 are acetylated and modulated by CBP and HDAC6 86 Figure 20. SIK2 kinase activity, controlled by an acetylation-based regulatory switch, contributes to the progression of autophagy 87 Figure 21. A hypothesized model suggests the possible role of SIK2 in the coordination of ERAD and autophagy 88 APPENDIX 1 89 FIGURE A1. The kinase activity of SIK2 is impaired by Lys53-acetylation (Chen, 2007) 90 FIGURE A2. SIK2 and p97/VCP colocalizes the TDP-43Δ inclusion bodies (Lin, 2009) 91 FIGURE A3. SIK2 is essential for the processing/removal of TDP-43Δ inclusion bodies (Lin, 2009) 92 FIGURE A4. Proteasome inhibition leads to SIK2 accumulation in insoluble fraction with ubiquitinated proteins (Lin, 2009) 93 FIGURE A5. SIK2 is deacetylated by HDAC6 in vitro (Sun, 2007) 94 FIGURE A6. Hsp90 is an important chaperone for SIK2 (Y. H. Lin, unpublished data) 95 FIGURE A7. SIK2 is activated under stress conditions (C. T. Chuang, unpublished data) 96 FIGURE A8. JNK-mediated activation of SIK2 under MG132 inhibition of proteasome (C. T. Chuang, unpublished data) 96 APPENDIX 2 97 | |
| dc.language.iso | en | |
| dc.subject | TDP-43 | zh_TW |
| dc.subject | HDAC6 | zh_TW |
| dc.subject | p300/CBP | zh_TW |
| dc.subject | 自噬 | zh_TW |
| dc.subject | 乙醯化 | zh_TW |
| dc.subject | SIK2 | zh_TW |
| dc.subject | TDP-43 | en |
| dc.subject | acetylation | en |
| dc.subject | autophagy | en |
| dc.subject | p300/CBP | en |
| dc.subject | HDAC6 | en |
| dc.subject | SIK2 | en |
| dc.title | 蛋白激酶SIK2的調控及其功能之研究 | zh_TW |
| dc.title | Regulation and Function of Protein Kinase SIK2 | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.coadvisor | 蔡明道 | |
| dc.contributor.oralexamcommittee | 陳瑞華,譚賢明,吳君泰 | |
| dc.subject.keyword | SIK2,乙醯化,自噬,p300/CBP,HDAC6,TDP-43, | zh_TW |
| dc.subject.keyword | SIK2,acetylation,autophagy,p300/CBP,HDAC6,TDP-43, | en |
| dc.relation.page | 109 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2013-03-18 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
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