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大学院医学系研究科（医学専攻等） 医学専攻 機能展開医学系 情報制御学・実験治療学講座 |
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Cargo receptor Surf4 regulates endoplasmic reticulum export of proinsulin in pancreatic β-cells
Saegusa K.
Communications Biology ( Communications Biology ) 5 ( 1 ) 2022年12月 [査読有り]
研究論文（学術雑誌）
Abstract
Insulin is an essential peptide hormone that maintains blood glucose levels. Although the mechanisms underlying insulin exocytosis have been investigated, the mechanism of proinsulin export from the endoplasmic reticulum (ER) remains unclear. Here, we demonstrated that Surf4, a cargo receptor homolog, regulates the ER export of proinsulin via its recruitment to ER exit sites (ERES). Under high-glucose conditions, Surf4 expression was upregulated, and Surf4 proteins mainly localized to the ER at a steady state and accumulated in the ERES, along with proinsulin in rat insulinoma INS-1 cells. Surf4-knockdown resulted in proinsulin retention in the ER and decreased the levels of mature insulin in secretory granules, thereby significantly reducing insulin secretion. Surf4 forms an oligomer and can physically interact with proinsulin and Sec12, essential for COPII vesicle formation. Our findings suggest that Surf4 interacts with proinsulin and delivers it into COPII vesicles for ER export in co-operation with Sec12 and COPII. -
Mitotic ER exit site dynamics: insights into blockade of secretion from the ER during mitosis
Maeda M.
Molecular and Cellular Oncology ( Molecular and Cellular Oncology ) 7 ( 6 ) 2020年11月 [査読有り]
研究論文（学術雑誌）
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Not just a cargo receptor for large cargoes; an emerging role of TANGO1 as an organizer of ER exit sites.
Saito, K. and Maeda, M.
J. Biochem. 166 ( 2 ) 115 - 119 2019年08月 [査読有り] [招待有り]
研究論文（学術雑誌） 国内共著
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LTK is an ER-resident receptor tyrosine kinase that regulates secretion.
Centonze, F.G., Reiterer, V., Nalbach, K., Saito, K., Pawlowski, K., Behrends, C. and Farhan, H.
J. Cell Biol. 218 ( 8 ) 2470 2019年06月 [査読有り]
研究論文（学術雑誌） 国内共著
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COPII proteins exhibit distinct subdomains within each ER exit site for executing their functions.
Maeda, M., Kurokawa, K., Katada, T., Nakano, A. and Saito, K.
Sci. Rep. 9 7346 2019年05月
研究論文（学術雑誌） 国内共著
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Kota Saito: Getting out and about
Marie Anne O’Donnell
J. Cell Biol. ( Rockfeller University Press ) 218 ( 6 ) 1765 2019年06月
総説・解説（学術雑誌） 単著
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Mitotic ER Exit Site Disassembly and Reassembly Are Regulated by the Phosphorylation Status of TANGO1
Kota Saito
Developmental Cell 2020年08月
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LTK is an ER-resident receptor tyrosine kinase that regulates secretion
Federica G. Centonze, Veronika Reiterer, Karsten Nalbach, Kota Saito, Krzysztof Pawlowski, Christian Behrends, Hesso Farhan
Journal of Cell Biology ( Rockefeller University Press ) 218 ( 8 ) 2470 - 2480 2019年06月
<jats:p>The endoplasmic reticulum (ER) is a key regulator of cellular proteostasis because it controls folding, sorting, and degradation of secretory proteins. Much has been learned about how environmentally triggered signaling pathways regulate ER function, but only little is known about local signaling at the ER. The identification of ER-resident signaling molecules will help gain a deeper understanding of the regulation of ER function and thus of proteostasis. Here, we show that leukocyte tyrosine kinase (LTK) is an ER-resident receptor tyrosine kinase. Depletion of LTK as well as its pharmacologic inhibition reduces the number of ER exit sites and slows ER-to-Golgi transport. Furthermore, we show that LTK interacts with and phosphorylates Sec12. Expression of a phosphoablating mutant of Sec12 reduces the efficiency of ER export. Thus, LTK-to-Sec12 signaling represents the first example of an ER-resident signaling module with the potential to regulate proteostasis.</jats:p>
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Kota Saito, Miharu Maeda
The Journal of Biochemistry ( Oxford University Press (OUP) ) 166 ( 2 ) 115 - 119 2019年05月
<jats:title>Abstract</jats:title>
<jats:p>Proteins synthesized within the endoplasmic reticulum (ER) are exported from ER exit sites via coat protein complex II (COPII)-coated vesicles. Although the mechanisms of COPII-vesicle formation at the ER exit sites are highly conserved among species, vertebrate cells secrete a wide range of materials, including collagens and chylomicrons, which form bulky structures within the ER that are too large to fit into conventional carriers. Transport ANd Golgi Organization 1 (TANGO1) was initially identified as a cargo receptor for collagens but has been recently rediscovered as an organizer of ER exit sites. We would like to review recent advances in the mechanism of large cargo secretion and organization of ER exit sites through the function of TANGO1.</jats:p> -
高等真核生物における巨大分子の分泌機構
齋藤 康太
生化学 ( 公益社団法人日本生化学会 ) 90 ( 5 ) 674 - 682 2018年10月
分泌タンパク質は小胞体で合成されたのち，COPII被覆小胞によってゴルジ体へ輸送される．COPII小胞の形成機構は出芽酵母からヒトに至るまで高度に保存されており，詳細に解析されてきた．一方で，高等真核生物に特有の分泌タンパク質の中には，コラーゲンやキロミクロンのように通常のCOPII小胞に入りきらない巨大な分子も存在する．このような巨大分子の分泌機構は，長らく不明であった．最近，巨大分子の分泌に特異的に関与する因子が相次いで報告され，そのメカニズムが解明されつつある．本稿では，我々の研究も含めて現在までに巨大分子の分泌機構について明らかになってきたこと，および今後の課題について概説する．
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Remodeling of ER‐exit sites initiates a membrane supply pathway for autophagosome biogenesis
Ge L, Zhang M, Kenny SJ, Liu D, Maeda M, Saito K, Mathur A, Xu K, Schekman R
EMBO reports ( {EMBO} ) 18 ( 9 ) 1586 - 1603 2017年09月
Autophagosomes are double-membrane vesicles generated during autophagy. Biogenesis of the autophagosome requires membrane acquisition from intracellular compartments, the mechanisms of which are unclear. We previously found that a relocation of COPII machinery to the ER-Golgi intermediate compartment (ERGIC) generates ERGIC-derived COPII vesicles which serve as a membrane precursor for the lipidation of LC3, a key membrane component of the autophagosome. Here we employed super-resolution microscopy to show that starvation induces the enlargement of ER-exit sites (ERES) positive for the COPII activator, SEC12, and the remodeled ERES patches along the ERGIC. A SEC12 binding protein, CTAGE5, is required for the enlargement of ERES, SEC12 relocation to the ERGIC, and modulates autophagosome biogenesis. Moreover, FIP200, a subunit of the ULK protein kinase complex, facilitates the starvation-induced enlargement of ERES independent of the other subunits of this complex and associates via its C-terminal domain with SEC12. Our data indicate a pathway wherein FIP200 and CTAGE5 facilitate starvation-induced remodeling of the ERES, a prerequisite for the production of COPII vesicles budded from the ERGIC that contribute to autophagosome formation.
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Cooper Geoffrey M., 榎森 康文, 足立 博之, 富重 道雄, 齋藤 康太, 須藤 和夫, 堅田 利明 ( 担当： 共訳 )
東京化学同人 2022年 ISBN: 9784807920259
学術書
学術関係受賞 【 表示 ／ 非表示 】
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日本生化学会奨励賞
2017年09月 日本生化学会
受賞者： 齋藤康太 -
柿内三郎記念奨励研究賞
2016年09月 日本生化学会
受賞者： 齋藤康太
科研費（文科省・学振）獲得実績 【 表示 ／ 非表示 】
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分泌経路を含むマルチステップを標的とした核酸医薬による肝線維化治療
挑戦的研究（開拓・萌芽）
研究期間: 2021年07月 - 2023年03月
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小胞体からの巨大分子分泌と外界シグナルによる分泌制御機構の解明
基盤研究(B)
研究期間: 2020年04月 - 2023年03月
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小胞体上の分泌ゾーンERESの局在決定機構 公募研究
新学術領域研究
研究期間: 2020年04月 - 2022年03月
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分泌経路に着目した肝線維化責任因子の同定と新規治療薬の開発
挑戦的研究（萌芽）
研究期間: 2019年06月 - 2021年03月
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コラーゲン分泌と小胞体出芽ドメインの形成に関与する新規膜複合体の機能解析
基盤研究(B)
研究期間: 2017年04月 - 2020年03月