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A study on the role of FKBP8 in mitochondrial fission and degradation : 미토콘드리아의 분열과 분해에서 FKBP8의 역할에 관한 연구
DC Field | Value | Language |
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dc.contributor.advisor | 정용근 | - |
dc.contributor.author | 유승민 | - |
dc.date.accessioned | 2017-10-27T17:11:57Z | - |
dc.date.available | 2018-10-25 | - |
dc.date.issued | 2017-08 | - |
dc.identifier.other | 000000145720 | - |
dc.identifier.uri | https://hdl.handle.net/10371/137142 | - |
dc.description | 학위논문 (박사)-- 서울대학교 대학원 자연과학대학 생명과학부, 2017. 8. 정용근. | - |
dc.description.abstract | Mitochondria change its shape continuously through fission and fusion which help to maintain functional mitochondria under metabolic or environmental stress condition. Dysfunction of such mitochondrial fusion and fission dynamics and degradation of mitochondria evokes failure of mitochondrial quality control and has been linked to several human diseases. Thus, identification of novel factor involved in mitochondrial dynamics and mitophagy are important and will provide mechanistic insight into mitochondria quality control. Here, I report that FKBP8, a FK506-binding protein 8 which is a member of the immunophilin protein family, has a critical role in mitochondrial fission and degradation. Ectopic expression of FKBP8 increased the numbers of cells showing mitochondrial fragmentation and induced drastic co-localization of GFP-LC3B as well as GFP-GABARAPL1 or GABARAPL2 with the mitochondria Deletion-mapping and mutagenesis analysis revealed that the N-terminal region was required for FKBP8-mediated LC3 recruitment onto mitochondria. Especially, the LIR#1 (24FEVL27) motif of FKBP8 was critical for the binding to LC3. Interestingly, ectopic expression of FKBP8 induced mitochondrial fragmentation and this ability was unique to FKBP8 among FKBP family. Conversely, knockdown of FKBP8 expression by RNA interference increased the volume and number of mitochondria. Especially, enlarged mitochondria was typically observed under electron microscope. FKBP8-induced mitochondrial fragmentation occurred independently of Drp1, BNIP3 and NIX, well known mitochondrial fission/mitophagic factors, but was abolished by mutation in the LIR#2 (93WLDI96). Further, I found that FKBP8 interacted with FIS1, a mitochondrial fission factor. But deletion in the LIR#2 (93WLDI96) or deletion in TPR domain of FKBP8 reduced the binding of FKBP8 to FIS1. In addition, knockdown of FKBP8 expression attenuated mitochondrial degradation under hypoxia. Together, these results suggest that FKBP8 mediates mitochondrial dynamics and degradation by binding to FIS1 through the LIR#2/TPR domain and perform mitophagic event by binding to LC3 through the LIR#1 motif. | - |
dc.description.tableofcontents | INTRODUCTION 1
RESULTS 7 Establishment of cell-based screening assay to isolate mitophagy regulator 7 Identification of FKBP8 as a GFP-LC3B recruiting factor to mitochondria 8 FKBP8 interacts with GFP-LC3B through its N-terminal to recruit it onto mitochondria 10 FKBP8 interacts with GFP-LC3B through LIR motif in the N-terminal region 12 FKBP8 affects mitochondrial fragmentation and fission 14 Of FKBP family, FKBP8 only affects mitochondrial dynamics 15 FKBP8 LIR#2, not FKBP8 LIR#1, is important for mitochondrial fragmentation 16 FKBP8 induces mitochondrial fragmentation in the absence of DRP1 17 Overexpression of FKBP8 induces mitophagy in BNIP3 and NIX knockout cells 18 FKBP8 interacts with FIS1 through LIR2 and TPR domains 19 Knockdown of FKBP8 reduces mitochondrial fragmentation and degradation in hypoxia 20 DISSCUSION 62 MATERIALS AND METHODS 67 DNA construction 61 Cell culture, DNA transfection and generation of stable cell line 68 Immunocytochemistry 68 Western blot and antibodies 69 Immunoprecipitation 69 Transmission electron microscope analysis 70 Statistics 70 REFERENCES 72 ABSTRACT IN KOREAN / 국문초록 84 | - |
dc.format | application/pdf | - |
dc.format.extent | 2434976 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | Mitophagy | - |
dc.subject | Autophagy | - |
dc.subject | Mitochondrial fission | - |
dc.subject | LIR | - |
dc.subject | FKBP8 | - |
dc.subject | LC3 | - |
dc.subject | FIS1 | - |
dc.subject.ddc | 570 | - |
dc.title | A study on the role of FKBP8 in mitochondrial fission and degradation | - |
dc.title.alternative | 미토콘드리아의 분열과 분해에서 FKBP8의 역할에 관한 연구 | - |
dc.type | Thesis | - |
dc.contributor.AlternativeAuthor | Seung-Min Yoo | - |
dc.description.degree | Doctor | - |
dc.contributor.affiliation | 자연과학대학 생명과학부 | - |
dc.date.awarded | 2017-08 | - |
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