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運動神経変性疾患の原因となる無糖鎖型Seipinに起因する小胞体ストレスと細胞死の誘導機構の解析

齊藤, 峻介 京都大学 DOI:10.14989/doctor.k24463

2023.03.23

概要

小胞体内に構造異常タンパク質が蓄積する小胞体ストレス状態が持続する
と、細胞機能が障害され、細胞死に至る場合もある。このような小胞体ストレ
スが神経変性疾患を発症させるのかどうかを究明することを目指し、本研究で
は遺伝性の神経変性疾患である Seipinopathy の原因となる変異遺伝子がコー
ドする、無糖鎖型 Seipin (ngSeipin : non-glycosylated Seipin)に着目した。
ngSeipin は他の著名な神経変性疾患の原因タンパク質とは異なり、小胞体膜に
局在する。また ngSeipin のトランスジェニックマウスの脳において小胞体ス
トレスが生じることもすでに明らかにされている。そこで、この ngSeipin が
導入された細胞の小胞体で何が起こって小胞体ストレスが生じるのか明らかに
できれば、小胞体ストレスに起因して神経変性疾患が起こるメカニズムを理解
するための手がかりが得られるのではないかと考え、解析を行った。
本研究では、ショウジョウバエ Seipin が小胞体膜カルシウムイオンポンプで
ある SERCA と結合し小胞体内へのカルシウムイオンの取り込みを促進すると
いう知見から着想を得て、ngSeipin が小胞体膜カルシウムイオンポンプの機能
に影響するかどうかを検討した。まずヒト大腸ガン由来細胞である HCT116 に
ngSeipin を導入したところ、導入量に相関して小胞体内カルシウムイオン濃度
が低下すると共に、小胞体ストレスと細胞死が誘導されることがわかった。
Seipin をノックアウトしたヒト神経芽細胞腫 SH-SY5Y に内在性 Seipin と同程
度の量の ngSeipin を導入した場合にも、同様の効果が見られた。このような小
胞体内カルシウムイオン濃度低下が生じるメカニズムをさらに詳細に検討した
ところ、ngSeipin はヒトの小胞体膜カルシウムイオンポンプである SERCA2b
を巻き込みながら小胞体膜上で凝集する性質があり、これにより SERCA2b が
不活 性化 され てしまう ことが 明ら か にな っ た 。さ ら に、 ngSeipin と 共 に
SERCA2b を発現させ、細胞内に存在する SERCA2b の総量を増やすことで小
胞体内カルシウムイオン濃度低下を補填すると、小胞体ストレスが減弱され、細
胞死も抑制されることを見出した。
以上の結果から、神経変性疾患の原因となる ngSeipin が小胞体内のカルシウ
ムイオン恒常性の維持を担う主要な分子の 1 つである SERCA2b の機能を直接
阻害し、小胞体ストレスと細胞死を引き起こすことを示すことができた。 ...

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参考文献

1.

Ellgaard L, Helenius A, Quality control in the endoplasmic reticulum.

Nature Reviews Molecular Cell Biology, (2003), 181-191, 4(3)

2.

Laude

A,

Simpson

A,

Compartmentalized

signalling:

Ca2+

compartments, microdomains and the many facets of Ca2+ signalling.

FEBS Journal, (2009), 1800-1816, 276(7)

3.

Brini M, Carafoli E, Calcium Pumps in Health and Disease. Physiol Rev

(2009), 89: 1341–1378,

4.

Berridge M, Bootman M, Roderick H, Calcium signalling: Dynamics,

homeostasis and remodeling. Nature Reviews Molecular Cell Biology,

(2003), 517-529, 4(7)

5.

Preissler S, Rato C, Yan Y, Perera L, Czako A, Ron D, Calcium depletion

challenges endoplasmic reticulum proteostasis by destabilising bipsubstrate complexes. eLife, (2020), 1-36, 9

6.

Mori K, Signalling pathways in the unfolded protein response:

Development from yeast to mammals. Journal of Biochemistry, (2009),

743-750, 146(6)

7.

Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic

interaction of BiP and ER stress transducers in the unfolded-protein

response. Nat Cell Biol. 2000. (2000), 2(6), 326-32,

8.

Harding H, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D,

Regulated

Translation

Initiation

Controls

Stress-Induced

Gene

Expression in Mammalian Cells. Molecular Cell, (2000), Vol. 6, 1099–

1108

73

9.

Harding H, Zhang Y, Ron D, Protein translation and folding are coupled

by an endoplasmic-reticulum-resident kinase. Nature, (1999), 397, 271274,

10. Kashiwagi K, Yokoyama T, Nishimoto M, Takahashi M, Sakamoto A,

Yonemochi M, Shirouzu M, Ito T, Structural basis for eIF2B inhibition in

integrated stress response. Science, (2019), 364, 495–499

11. Vattem K, Wek R, Reinitiation involving upstream ORFs regulates ATF4

mRNA translation in mammalian cells. PNAS, (2004), vol. 101, no. 31,

11269 –11274

12. Oyadomari S, Mori M, Roles of CHOP/GADD153 in endoplasmic

reticulum stress. Cell death and Differentiation, (2004), 11(4), 381-389,

13. Harding H, Zhang Y, Zeng H, Novoa I, Lu P, Calfon M, Sadri N, Yun C,

Popko B, Paules R, Stojdl D, Bell J, Hettmann T, Leiden J, Ron D, An

Integrated Stress Response Regulates Amino Acid Metabolism and

Resistance to Oxidative Stress. Molecula Cell, (2003), Vol. 11, 619-633

14. Harding H, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, Sabatini

D, Ron D, Diabetes Mellitus and Exocrine Pancreatic Dysfunction in

Perk/ Mice Reveals a Role for Translational Control in Secretory Cell

Survival.

Molecular Cell, (2001), Vol. 7, 1153–1163,

15. Yoshida H, Haze K, Yanagi H, Yura T, Mori K, Identification of the cisacting endoplasmic reticulum stress response element responsible for

transcriptional induction of mammalian glucose- regulated proteins:

Involvement of basic leucine zipper transcription factors. Journal of

Biological Chemistry, (1998), 33741-33749, 273(50)

74

16. Haze K, Yoshida H, Yanagi H, Yura T, Mori K, Mammalian Transcription

Factor ATF6 Is Synthesized as a Transmembrane Protein and Activated

by Proteolysis in Response to Endoplasmic Reticulum Stress. Molecular

Biology of the Cell, (1999), Vol. 10, 3787–3799,

17. Ye J, Rawson R, Komuro R, Chen X, Davé U, Prywes R, Brown M,

Goldstein J, ER Stress Induces Cleavage of Membrane-Bound ATF6 by

the Same Proteases that Process SREBPs. Molecular Cell, (2000), Vol. 6,

1355–1364,

18. Okada T, Haze K, Nadanaka S, Yoshida H, Seidah N, Hirano Y, Sato R,

Negishi M, Mori K, A serine protease inhibitor prevents endoplasmic

reticulum stress-induced cleavage but not transport of the membranebound transcription factor ATF6. Journal of Biological Chemistry, (2003),

31024-31032, 278(33)

19. Yoshida H, Okada T, Haze K, Yanagi H, Yura T, Negishi M, Mori K,

Endoplasmic Reticulum Stress-Induced Formation of Transcription

Factor

Complex

ERSF

Including

NF-Y

(CBF)

and

Activating

Transcription Factors 6α and 6β That Activates the Mammalian

Unfolded Protein Response. Molecular and Cellular Biology, (2001), 12391248, 21(4)

20. Okada T, Yoshida H, Akazawa R, Negishi M, Mori K, Distinct roles of

activating transcription factor 6 (ATF6) and double-stranded RNAactivated protein kinase-like endoplasmic reticulum kinase (PERK) in

transcription during the mammalian unfolded protein response. Biochem.

J., (2002), 366, 585–594,

21. Adachi Y, Yamamoto K, Okada T, Yoshida H, Harada A, Mori K, (2008),

ATF6 Is a Transcription Factor Specializing in the Regulation of Quality

Control Proteins in the Endoplasmic Reticulum. CELL STRUCTURE

AND FUNCTION, (2008), 33: 75–89

75

22. Ishikawa T, Okada T, Ishikawa-Fujiwara T, Todo T, Kamei Y, Shigenobu

S, Tanaka M, Saito T, Yoshimura J, Morishita S, Toyoda A, Sakaki Y,

Taniguchi Y, Takeda S, Mori K, ATF6α/β-mediated adjustment of ER

chaperone levels is essential for development of the notochord in medaka

fish. Molecular Biology of the Cell, (2013), 1387-1395, 24(9)

23. Haze K, Okada T, Yoshida H, Yanagi H, Yura T, Negishi M, Mori K,

Identification of the G13 (cAMP-response-element-binding proteinrelated protein) gene product related to activating transcription factor 6

as a transcriptional activator of the mammalian unfolded protein

response.

Biochem J., (2001), 355, 19–28,

24. Ishikawa T, Taniguchi Y, Okada T, Takeda S, Mori K, Vertebrate

Unfolded Protein Response: Mammalian Signaling Pathways Are

Conserved in Medaka Fish. CELL STRUCTURE AND FUNCTION,

(2011), 36: 247–259,

25. Yamamoto K, Sato T, Matsui T, Sato M, Okada T, Yoshida H, Harada A,

Mori K, Transcriptional Induction of Mammalian ER Quality Control

Proteins Is Mediated by Single or Combined Action of ATF6α and XBP1.

Developmental Cell, (2007), 365-376, 13(3)

26. Tirasophon W, Welihinda A, Kaufman R, A stress response pathway from

the endoplasmic reticulum to the nucleus requires a novel bifunctional

protein kinase/endoribonuclease (Ire1p) in mammalian cells. GENES &

DEVELOPMENT, (1998), 12:1812–1824

27. Wang X, Harding H, Zhang Y, Jolicoeur E, Kuroda M, Ron D, Cloning of

mammalian Ire1 reveals diversity in the ER stress responses. EMBO

Journal, (1998), 5708-5717, 17(19)

76

28. Lu Y, Liang F, Wang X, A Synthetic Biology Approach Identifies the

Mammalian UPR RNA Ligase RtcB. Molecular Cell, (2014), 758-770,

55(5)

29. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K, XBP1 mRNA Is

Induced by ATF6 and Spliced by IRE1 in Response to ER Stress to

Produce a Highly Active Transcription Factor. Cell, (2001), Vol. 107, 881–

891,

30. Yamamoto K, Yoshida H, Kokame K, Kaufman R, Mori K, Differential

Contributions of ATF6 and XBP1 to the Activation of Endoplasmic

Reticulum Stress-Responsive cis-Acting Elements ERSE, UPRE and

ERSE-II, J. Biochem, (2004), 343-350, 136

31. Yoshida H, Matsui T, Hosokawa N, Kaufman R, Nagata K, Mori K, A

Time-Dependent Phase Shift in the Mammalian Unfolded Protein

Response to decrease the load in the ER; these processes are collectively

termed the unfolded protein response. Developmental Cell, (2003), Vol. 4,

265–271,

32. Yamamoto K, Suzuki N, Wada T, Okada T, Yoshida H, Kaufman R, Mori

K, Human HRD1 promoter carries a functional unfolded protein response

element to which XBP1 but not ATF6 directly binds. Journal of

Biochemistry, (2008), 477-486, 144(4)

33. Liu L, Cai J, Wang H, Liang X, Zhou Q, Ding C, Zhu Y, Fu T, Guo Q, Xu

Z, Xiao L, Liu J, Yin Y, Fang L, Xue B, Wang Y, Meng Z, He A, Li J, Liu

Y, Chen X, Gan Z, Coupling of COPII vesicle trafficking to nutrient

availability by the IRE1α-XBP1s axis. Proceedings of the National

Academy of Sciences of the United States of America, (2019), 1177611785, 116(24)

77

34. Bertolotti A, Wang X, Novoa I, Jungreis R, Schlessinger K, Cho J, West

A, Ron D, Increased sensitivity to dextran sodium sulfate colitis in

IRE1β-deficient mice. Journal of Clinical Investigation, (2001), 585-593,

107(5)

35. Iwawaki T, Akai R, Yamanaka S, Kohno K, Function of IRE1 alpha in the

placenta is essential for placental development and embryonic viability.

PNAS, (2009), vol. 106, no. 39, 16657–16662,

36. Zhang K, Wong H, Song B, Miller C, Scheuner D, Kaufman R, The

unfolded protein response sensor IRE1α is required at 2 distinct steps in

B cell lymphopoiesis. Journal of Clinical Investigation, (2005), 268-281,

115(2)

37. Ishikawa T, Kashima M, Nagano A, Ishikawa-Fujiwara T, Kamei Y, Todo

T, Mori K, Unfolded protein response transducer IRE1-mediated

signaling independent of XBP1 mRNA splicing is not required for growth

and development of medaka fish. eLife, (2017), 6

38. Carrara M, Prischi F, Ali M, UPR signal activation by luminal sensor

domains. International Journal of Molecular Sciences, (2013), 6454-6466,

14(3)

39. Carrara M, Prischi F, Nowak P, Kopp M, Ali M, Noncanonical binding of

BiP ATPase domain to Ire1 and Perk is dissociated by unfolded protein C

H 1 to initiate ER stress signaling. eLife, (2015), 4

40. Kay L, Elif K, aragö G, Acosta-Alvear D, Nguyen H, Lee C, Chu F, Walter

P, An unfolded protein-induced conformational switch activates

mammalian IRE1. eLife, (2017), 6

78

41. Oikawa D, Kitamura A, Kinjo M, Iwawaki T, Direct Association of

Unfolded Proteins with Mammalian ER Stress Sensor, IRE1β. PLoS ONE,

(2012), 7(12)

42. Wang P, Li J, Sha B, The ER stress sensor PERK luminal domain

functions as a molecular chaperone to interact with misfolded proteins.

Acta Crystallographica Section D: Structural Biology, (2016), 1290-1297,

72(12)

43. Wang P, Li J, Tao J, Sha B, The luminal domain of the ER stress sensor

protein PERK binds misfolded proteins and thereby triggers PERK

oligomerization. Journal of Biological Chemistry, (2018), 4110-4121,

293(11)

44. McCullough K, Martindale J, Klotz L, Aw T, Holbrook N, Gadd153

Sensitizes Cells to Endoplasmic Reticulum Stress by Down-Regulating

Bcl2 and Perturbing the Cellular Redox State. Molecular and Cellular

Biology, (2001), 1249-1259, 21(4)

45. Puthalakath H, O'Reilly L, Gunn P, Lee L, Kelly P, Huntington N,

Hughes P, Michalak E, McKimm-Breschkin J, Motoyama N, Gotoh T,

Akira S, Bouillet P, Strasser A, ER Stress Triggers Apoptosis by

Activating BH3-Only Protein Bim. Cell, (2007), 1337-1349, 129(7)

46. Kim H, Tu H, Ren D, Takeuchi O, Jeffers J, Zambetti G, Hsieh J, Cheng

E, Stepwise Activation of BAX and BAK by tBID, BIM, and PUMA

Initiates Mitochondrial Apoptosis. Molecular Cell, (2009), 487-499, 36(3)

47. Masud A, Mohapatra A, Lakhani S, Ferrandino A, Hakem R, Flavell R,

Endoplasmic reticulum stress-induced death of mouse embryonic

fibroblasts requires the intrinsic pathway of apoptosis. Journal of

Biological Chemistry, (2007), 14132-14139, 282(19)

79

48. Yamaguchi H, Wang H, CHOP is involved in endoplasmic reticulum

stress-induced apoptosis by enhancing DR5 expression in human

carcinoma cells. Journal of Biological Chemistry, (2004), 45495-45502,

279(44)

49. Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H, TRB3, a novel ER

stress-inducible gene, is induced via ATF4-CHOP pathway and is

involved in cell death. EMBO Journal, (2005), 1243-1255, 24(6)

50. Cazanave S, Elmi N, Akazawa Y, Bronk S, Mott J, Gores G, CHOP and

AP-1 cooperatively mediate PUMA expression during lipoapoptosis.

American Journal of Physiology - Gastrointestinal and Liver Physiology,

(2010), 299(1)

51. Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K,

Hori S, Kakizuka A, Ichijo H, ASK1 is essential for endoplasmic

reticulum stress-induced neuronal cell death triggered by expanded

polyglutamine repeats. Genes and Development, (2002), 1345-1355,

16(11)

52. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding H, Ron D,

Coupling of stress in the ER to activation of JNK protein kinases by

transmembrane. protein kinase IRE1. Science, (2000), 664-666, 287(5453)

53. Julie H, Jonathan S. W, Decay of EndoplasmicReticulum-Localized

mRNAs Duringthe Unfolded Protein Response. Science, (2006), 104-107,

313 (5783)

54. Upton J, Wang L, Han D, Wang E, Huskey N, Lim L, Truitt M, McManus

M, Ruggero D, Goga A, Papa F, Oakes S, IRE1α cleaves select microRNAs

during ER stress to derepress translation of proapoptotic caspase-2.

Science, (2012), 818-822, 338(6108)

80

55. Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, Liu

K, Xu K, Strathearn KE, Liu F, Cao S, Caldwell KA, Caldwell GA,

Marsischky G, Kolodner RD, Labaer J, Rochet JC, Bonini NM, Lindquist

S. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss

in Parkinson's models. Science. 2006 Jul 21;313(5785):324-8.

56. Nishitoh H, Kadowaki H, Nagai A, Maruyama T, Yokota T, Fukutomi H,

Noguchi T, Matsuzawa A, Takeda K, Ichijo H, ALS-linked mutant SOD1

induces ER stress- and ASK1-dependent motor neuron death by

targeting Derlin-1. Genes and Development, (2008), 1451-1464, 22(11)

57. Windpassinger C, Auer-Grumbach M, Irobi J, Patel H, Petek E, Hörl G,

Malli R, Reed J, Dierick I, Verpoorten N, Warner T, Proukakis C, Van

Den Bergh P, Verellen C, Van Maldergem L, Merlini L, De Jonghe P,

Timmerman V, Crosby A, Wagner K, Heterozygous missense mutations

in BSCL2 are associated with distal hereditary motor neuropathy and

Silver syndrome. Nature Genetics, (2004), 271-276, 36(3)

58. Ito D, Suzuki N, Seipinopathy: A novel endoplasmic reticulum stressassociated disease. Brain, (2009), 8-15, 132(1)

59. Yan R, Qian H, Lukmantara I, Gao M, Du X, Yan N, Yang H, Human

SEIPIN Binds Anionic Phospholipids. Developmental Cell, (2018), 248256.e4, 47(2)

60. Sui X, Arlt H, Brock K, Lai Z, DiMaio F, Marks D, Liao M, Farese R,

Walther T, Cryo–electron microscopy structure of the lipid droplet–

formation protein seipin. Journal of Cell Biology, (2018), 4080-4091,

217(12)

61. Klug Y, Deme J, Corey R, Renne M, Stansfeld P, Lea S, Carvalho P,

Mechanism of lipid droplet formation by the yeast Sei1/Ldb16 Seipin

complex. Nature Communications, (2021), 12(1)

81

62. Arlt H, Sui X, Folger B, Adams C, Chen X, Remme R, Hamprecht FA,

DiMaio F, Liao M, Goodman JM, Farese RV Jr, Walther TC. Seipin forms

a flexible cage at lipid droplet formation sites. Nature Structural and

Molecular Biology, (2022), 194-202, 29(3)

63. Magré J, Delépine M, Khallouf E, Gedde-Dahl T Jr, Van Maldergem L,

Sobel E, Papp J, Meier M, Mégarbané A, Bachy A, Verloes A, d'Abronzo

FH, Seemanova E, Assan R, Baudic N, Bourut C, Czernichow P, Huet F,

Grigorescu F, de Kerdanet M, Lacombe D, Labrune P, Lanza M, Loret H,

Matsuda F, Navarro J, Nivelon-Chevalier A, Polak M, Robert JJ, Tric P,

Tubiana-Rufi N, Vigouroux C, Weissenbach J, Savasta S, Maassen JA,

Trygstad O, Bogalho P, Freitas P, Medina JL, Bonnicci F, Joffe BI, Loyson

G, Panz VR, Raal FJ, O'Rahilly S, Stephenson T, Kahn CR, Lathrop M,

Capeau J; BSCL Working Group. Identification of the gene altered in

Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.

Nature Genetics, (2001), 365-370, 28(4)

64. Szymanski K, Binns D, Bartz R, Grishin N, Li W, Agarwal A, Garg A W,

Anderson R, Goodman J, The lipodystrophy protein seipin is found at

endoplasmic reticulum lipid droplet junctions and is important for

droplet morphology. PNAS, (2007), 04(52):20890-5.

65. Tian Y, Bi J, Shui G, Liu Z, Xiang Y, Liu Y, Wenk M, Yang H, Huang X,

Tissue-autonomous function of drosophila seipin in preventing ectopic

lipid droplet formation. PLoS Genetics, (2011), 7(4)

66. Salo V, Belevich I, Li S, Karhinen L, Vihinen H, Vigouroux C, Magré J,

Thiele C, Hölttä‐Vuori M, Jokitalo E, Ikonen E, Seipin regulates ER –

lipid droplet contacts and cargo delivery, The EMBO Journal, (2016),

2699-2716, 35(24)

67. Ito D, Suzuki N, Molecular pathogenesis of Seipin/BSCL2-related motor

neuron diseases. Annals of Neurology, (2007), 237-250, 61(3)

82

68. Yagi T, Ito D, Nihei Y, Ishihara T, Suzuki N, N88S seipin mutant

transgenic mice develop features of seipinopathy/BSCL2-related motor

neuron disease via endoplasmic reticulum stress. Human Molecular

Genetics, (2011), 3831-3840, 20(19)

69. Bi J, Wang W, Liu Z, Hueng X, Jiang Q, Liu G, Wang Y, Huang X, Seipin

promotes adipose tissue fat storage through the ER Ca 2+-ATPase

SERCA. Cell Metabolism, (2014), 861-871, 19(5)

70. Roschke A, Stover K, Tonon G, Schäffer A, Kirsch I, Stable karyotypes in

epithelial cancer cell lines despite high rates of ongoing structural and

numerical chromosomal instability. Neoplasia, (2002), 19-31, 4(1)

71. Yusuf M, Leung K, Morris K, Volpi E, Comprehensive cytogenomic profile

of the in vitro neuronal model SH-SY5Y. Neurogenetics, (2013), 63-70,

14(1)

72. Lundin C, Nordström R, Wagner K, Windpassinger C, Andersson H, von

Heijne G, Nilsson I, Membrane topology of the human seipin protein.

FEBS Letters, (2006), 2281-2284, 580(9)

73. Gélébart P, Martin V, Enouf J, Papp B, Identification of a new SERCA2

splice variant regulated during monocytic differentiation. Biochemical

and Biophysical Research Communications, (2003), 676-684, 303(2)

74. Dally S, Bredoux R, Corvazier E, Andersen J, Clausen J, Dode L,

Fanchaouy M, Gelebart P, Monceau V, Del Monte F, Gwathmey J, Hajjar

R, Chaabane C, Bobe R, Raies A, Enouf J, Ca2+-ATPases in non-failing

and failing heart: Evidence for a novel cardiac sarco/endoplasmic

reticulum Ca2+-ATPase 2 isoform (SERCA2c). Biochemical Journal,

(2006), 249-258, 395(2)

83

75. GTEx Consortium. Human genomics. The Genotype-Tissue Expression

(GTEx) pilot analysis: multitissue gene regulation in humans. Science,

(2015), May 8;348(6235):648-60.

76. Papatheodorou I, Moreno P, Manning J, Fuentes AM, George N, Fexova

S, Fonseca NA, Füllgrabe A, Green M, Huang N, Huerta L, Iqbal H, Jianu

M, Mohammed S, Zhao L, Jarnuczak AF, Jupp S, Marioni J, Meyer K,

Petryszak R, Prada Medina CA, Talavera-López C, Teichmann S,

Vizcaino JA, Brazma A. Expression Atlas update: from tissues to single

cells. Nucleic Acids Research, (2020), D77-D83, 48(D1)

77. Suzuki J, Kanemaru K, Ishii K, Ohkura M, Okubo Y, Iino M, Imaging

intraorganellar Ca2+ at subcellular resolution using CEPIA. Nature

Communications, (2014), 5

78. Chen T, Wardill T, Sun Y, Pulver S, Renninger S, Baohan A, Schreiter E,

Kerr R, Orger M, Jayaraman V, Looger L, Svoboda K, Kim D,

Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature,

(2013), 295-300, 499(7458)

79. Lyttonsg J, Westlins M, Hanleyll M, Thapsigargin Inhibits the

Sarcoplasmic or Endoplasmic Reticulum Ca-ATPase Family of Calcium

Pumps*. THE JOURNAL OF BIOLOGICAL CHEMISTRY, (1991),

17067-17071,

80. Zorzato F, Scutari E, Tegazzin V, Clementi E, Treves S. Chlorocresol: an

activator of ryanodine receptor-mediated Ca2+ release. Mol Pharmacol,

(1993), 44(6), 1192-201,

81. Cruzblanca H, Koh D, Hille B, Bradykinin inhibits M current via

phospholipase C and Ca 2 release from IP 3-sensitive Ca 2 stores in rat

sympathetic neurons. PNAS, (1998), 7151-7156

84

82. Cornea R, Gruber S, Lockamy E, Muretta J, Jin D, Chen J, Dahl R,

Bartfai T, Zsebo K, Gillispie G, Thomas D, High-throughput FRET assay

yields allosteric SERCA activators. Journal of Biomolecular Screening,

(2013), 97-107, 18(1)

83. Gruber S, Cornea R, Li J, Peterson K, Schaaf T, Gillispie G, Dahl R, Zsebo

K, Robia S, Thomas D, Discovery of enzyme modulators via highthroughput time-resolved FRET in living cells. Journal of Biomolecular

Screening, (2014), 215-222, 19(2)

84. Abrenica B, Gilchrist J, Nucleoplasmic Ca2+ loading is regulated by

mobilization of perinuclear Ca2+. Cell Calcium, (2000), 127-136, 28(2)

85. Miyauchi Y, Daiho T, Yamasaki K, Takahashi H, Ishida-Yamamoto A,

Danko S, Suzuki H, Iizuka H, Comprehensive analysis of expression and

function of 51 sarco(endo)plasmic reticulum Ca2+-ATPase mutants

associated with darier disease. Journal of Biological Chemistry, (2006),

22882-22895, 281(32)

86. Gaudelli N, Komor A, Rees H, Packer M, Badran A, Bryson D, Liu D,

Programmable base editing of T to G C in genomic DNA without DNA

cleavage. Nature, (2017), 464-471, 551(7681)

87. Komor A, Zhao K, Packer M, Gaudelli N, Waterbury A, Koblan L, Kim Y,

Badran A, Liu D, Improved base excision repair inhibition and

bacteriophage Mu Gam protein yields C:G-to-T:A base editors with

higher efficiency and product purity. Sci Adv, (2017), 3(8), eaao4774,

88. Richardson C, Ray G, DeWitt M, Curie G, Corn J, Enhancing homologydirected genome editing by catalytically active and inactive CRISPRCas9 using asymmetric donor DNA. Nature Biotechnology, (2016), 339344, 34(3)

85

89. Kim S, Matsumoto T, Kagawa H, Nakamura M, Hirohata R, Ueno A,

Ohishi M, Sakuma T, Soga T, Yamamoto T, Woltjen K, Microhomologyassisted

scarless

genome

editing

in

human

iPSCs.

Nature

Communications, (2018), 9(1)

90. Fei W, Shui G, Gaeta B, Du X, Kuerschner L, Li P, Brown A, Wenk M,

Parton R, Yang H, Fld1p, a functional homologue of human seipin,

regulates the size of lipid droplets in yeast. Journal of Cell Biology, (2008),

473-482, 180(3)

91. Wang C, Miao Y, Chang Y, Control of lipid droplet size in budding yeast

requires the collaboration between Fld1 and Ldb16. Journal of Cell

Science, (2014), 1214-1228, 127(6)

92. Cranfill P, Sell B, Baird M, Allen J, Lavagnino Z, De Gruiter H, Kremers

G, Davidson M, Ustione A, Piston D, Quantitative assessment of

fluorescent proteins. Nature Methods, (2016), 557-562, 13(7)

93. Ebihara K, Kusakabe T, Masuzaki H, Kobayashi N, Tanaka T, Chusho H,

Miyanaga F, Miyazawa T, Hayashi T, Hosoda K, Ogawa Y, Nakao K, Gene

and Phenotype Analysis of Congenital Generalized Lipodystrophy in

Japanese: A Novel Homozygous Nonsense Mutation in Seipin Gene.

Journal of Clinical Endocrinology and Metabolism, (2004), 2360-2364,

89(5)

94. Yang W, Thein S, Guo X, Xu F, Venkatesh B, Sugii S, Radda G, Han W,

Seipin differentially regulates lipogenesis and adipogenesis through a

conserved core sequence and an evolutionarily acquired C-terminus.

Biochemical Journal, (2013), 37-44, 452(1)

86

95. Paganoni S, Macklin EA, Hendrix S, Berry JD, Elliott MA, Maiser S,

Karam C, Caress JB, Owegi MA, Quick A, Wymer J, Goutman SA,

Heitzman D, Heiman-Patterson T, Jackson CE, Quinn C, Rothstein JD,

Kasarskis EJ, Katz J, Jenkins L, Ladha S, Miller TM, Scelsa SN, Vu TH,

Fournier CN, Glass JD, Johnson KM, Swenson A, Goyal NA, Pattee GL,

Andres PL, Babu S, Chase M, Dagostino D, Dickson SP, Ellison N, Hall

M, Hendrix K, Kittle G, McGovern M, Ostrow J, Pothier L, Randall R,

Shefner JM, Sherman AV, Tustison E, Vigneswaran P, Walker J, Yu H,

Chan J, Wittes J, Cohen J, Klee J, Leslie K, Tanzi RE, Gilbert W,

Yeramian PD, Schoenfeld D, Cudkowicz ME. Trial of Sodium

Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis. New

England Journal of Medicine, (2020), 919-930, 383(10)

96. Paganoni S, Hendrix S, Dickson SP, Knowlton N, Macklin EA, Berry JD,

Elliott MA, Maiser S, Karam C, Caress JB, Owegi MA, Quick A, Wymer

J, Goutman SA, Heitzman D, Heiman-Patterson TD, Jackson CE, Quinn

C, Rothstein JD, Kasarskis EJ, Katz J, Jenkins L, Ladha S, Miller TM,

Scelsa SN, Vu TH, Fournier CN, Glass JD, Johnson KM, Swenson A,

Goyal NA, Pattee GL, Andres PL, Babu S, Chase M, Dagostino D, Hall

M, Kittle G, Eydinov M, McGovern M, Ostrow J, Pothier L, Randall R,

Shefner JM, Sherman AV, St Pierre ME, Tustison E, Vigneswaran P,

Walker J, Yu H, Chan J, Wittes J, Yu ZF, Cohen J, Klee J, Leslie K, Tanzi

RE, Gilbert W, Yeramian PD, Schoenfeld D, Cudkowicz ME. Long-term

survival of participants in the CENTAUR trial of sodium phenylbutyratetaurursodiol in amyotrophic lateral sclerosis. Muscle Nerve, (2021), 63(1),

31-39,

97. Sambrook, J., Fritsch, E. R., & Maniatis, T. (1989). Molecular Cloning: A

Laboratory Manual (2nd ed.). Cold Spring Harbor, NY: Cold Spring

Harbor Laboratory Press.

87

98. George G, Ninagawa S, Yagi H, Furukawa J, Hashii N, Ishii-Watabe A,

Deng Y, Matsushita K, Ishikawa T, Mamahit Y, Maki Y, Kajihara Y, Kato

K, Okada T, Mori K, Purified EDEM3 or EDEM1 alone produces

determinant oligosaccharide structures from M8B in mammalian

glycoprotein ERAD. eLife, (2021), 70357, 10

99. Van Engelenburg S, Palmer A, Imaging type-III secretion reveals

dynamics and spatial segregation of Salmonella effectors. Nature

Methods, (2010), 325-330, 7(4)

100. Ninagawa S, Okada T, Sumitomo Y, Kamiya Y, Kato K, Horimoto S,

Ishikawa T, Takeda S, Sakuma T, Yamamoto T, Mori K, EDEM2 initiates

mammalian glycoprotein ERAD by catalyzing the first mannose

trimming step. Journal of Cell Biology, (2014), 347-356, 206(3)

88

謝辞

本研究を行う機会を与えて頂き、終始ご指導・ご鞭撻を賜りました京都大学大

生物物理学教室

学院理学研究科

ゲノム情報発現学分野

教授

森和俊

士に謹んで深謝の意を表します。森教授には 2014 年 4 月から 9 年間もの間、何

不自由なく研究に徹することのできる環境と、数えきれないほど多くの有益な

助言を与えていただきました。また、絶えず真摯に熱心に研究と向き合う姿勢か

ら多くの大切なことを学ばせていただき、私に研究者として目指すべき姿を示

してくださいました。

同分野

助教

岡田徹也

博士には、研究の多くの局面で様々な角度からご

助言をいただきました。また本研究の完成のために欠かすことのできなかった

顕微鏡解析のための詳細な技術と知識を授けていただきました。この場を借り

て深く感謝申し上げます。

同分野

助教でいらっしゃいました、住友化学株式会社

細胞生化学 G

細胞技術 T 主任研究員

石川時郎

生物環境科学研究

博士には、私が森研

究室に所属して以降、最も身近な立場で数多くの実験・解析の方法を教えてい

ただきました。また、論文のデータの解釈の仕方や研究の進め方など、研究者

として生きていくための思考方法の基礎を授けていただきました。それだけで

なく、研究に挫折しくじけそうになった私を何度も励まし、支えてくださいま

した。深く感謝申し上げます。

特定助教でいらっしゃいました、神戸大学バイオシグナル総合研究

同分野

センター、農学研究科資源生命科学専攻

蜷川

応用動物学講座細胞情報学

助教

博士には、研究にあたり数多くの局面でご相談させていただき、い

つも的確なアドバイスをしていただきました。また日頃から親身に接していた

だき、沢山の励ましの言葉もいただきました。深く感謝いたします。

森研究室の皆様には様々なご助言をいただき、色々な場面でお世話になりま

した。宮川かおるさんには研究試薬の調製や事務の仕事で日々お世話になりま

した。澤田眞紀子さんにはメダカの飼育・維持をしていただきました。皆様の

多大な支援をいただき、大変有意義な研究生活を送ることができました。あり

がとうございました。

最後に、研究に取り組む自由を与え、いつも心の支えとなってくれた

修、母

早苗、弟

航介、妹

あかね、祖母

89

とき子に感謝いたします。

...

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