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Faculty of Medicine School of Medicine Department of Medical Sciences, Biochemistry and Molecular Biology |
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Assistant Professor |
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Related SDGs |
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KADOWAKI Hisae
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Research Areas 【 display / non-display 】
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Life Science / Oral pathobiological science
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Life Science / Functional biochemistry
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Life Science / Medical biochemistry
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Life Science / Cell biology
Papers 【 display / non-display 】
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Sec61β maintains cytoplasmic proteostasis via ARIH1-mediated translational repression upon ER stress Reviewed
Hisae Kadowaki, Tomohisa Hatta, Kazuma Sugiyama, Tomohiro Fukaya, Takao Fujisawa, Takashi Hamano, Naoya Murao, Yasunari Takami, Shuya Mitoma, Tohru Natsume, Katsuaki Sato, Hiromi Hirata, Tamayo Uechi, Hideki Nishitoh
EMBO Reports 27 ( 4 ) 1057 - 1091 2026.1
Authorship：Lead author, Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：EMBO Reports
Disrupted proteostasis causes various degenerative diseases, and organelle homeostasis is therefore maintained by elaborate mechanisms. Endoplasmic reticulum (ER) stress-induced preemptive quality control (ERpQC) counteracts stress by reducing ER load through inhibiting the translocation of newly synthesized proteins into the ER for their rapid degradation in the cytoplasm. Here, we show that Sec61β, a translocon component, prevents the overproduction of ERpQC substrates, allowing for their efficient degradation by the proteasome. Sec61β inhibits the binding of translation initiation factor eIF4E to the mRNA 5ʹ cap structure by recruiting E3 ligase ARIH1 and eIF4E-homologous protein 4EHP, resulting in selective translational repression of ERpQC substrates. Sec61β deficiency causes overproduction of ERpQC substrates and reduces proteasome activity, leading to cytoplasmic aggresome formation. We also show that Sec61β deficiency causes motor dysfunction in zebrafish, which is restored by exogenous ARIH1 expression. Collectively, translational repression of ERpQC substrates by the Sec61β–ARIH1 complex contributes to maintain ER and cytoplasmic proteostasis.
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Shiiba I., Ito N., Oshio H., Ishikawa Y., Nagao T., Shimura H., Oh K.W., Takasaki E., Yamaguchi F., Konagaya R., Kadowaki H., Nishitoh H., Tanzawa T., Nagashima S., Sugiura A., Fujikawa Y., Umezawa K., Tamura Y., Il Lee B., Hirabayashi Y., Okazaki Y., Sawa T., Inatome R., Yanagi S.
Nature Communications 16 ( 1 ) 1508 2025.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Communications
The proximal domains of mitochondria and the endoplasmic reticulum (ER) are linked by tethering factors on each membrane, allowing the efficient transport of substances, including lipids and calcium, between them. However, little is known about the regulation and function of mitochondria-ER contacts (MERCs) dynamics under mitochondrial damage. In this study, we apply NanoBiT technology to develop the MERBiT system, which enables the measurement of reversible MERCs formation in living cells. Analysis using this system suggests that induction of mitochondrial ROS increases MERCs formation via RMDN3 (also known as PTPIP51)-VAPB tethering driven by RMDN3 phosphorylation. Disruption of this tethering caused lipid radical accumulation in mitochondria, leading to cell death. The lipid radical transfer activity of the TPR domain in RMDN3, as revealed by an in vitro liposome assay, suggests that RMDN3 transfers lipid radicals from mitochondria to the ER. Our findings suggest a potential role for MERCs in cell survival strategy by facilitating the removal of mitochondrial lipid radicals under mitochondrial damage.
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The Derlin-1-Stat5b axis maintains homeostasis of adult hippocampal neurogenesis Reviewed
Murao N., Matsuda T., Kadowaki H., Matsushita Y., Tanimoto K., Katagiri T., Nakashima K., Nishitoh H.
EMBO Reports 25 ( 8 ) 3678 - 3706 2024.8
Language：English Publishing type：Research paper (scientific journal) Publisher：EMBO Reports
Adult neural stem cells (NSCs) in the hippocampal dentate gyrus continuously proliferate and generate new neurons throughout life. Although various functions of organelles are closely related to the regulation of adult neurogenesis, the role of endoplasmic reticulum (ER)-related molecules in this process remains largely unexplored. Here we show that Derlin-1, an ER-associated degradation component, spatiotemporally maintains adult hippocampal neurogenesis through a mechanism distinct from its established role as an ER quality controller. Derlin-1 deficiency in the mouse central nervous system leads to the ectopic localization of newborn neurons and impairs NSC transition from active to quiescent states, resulting in early depletion of hippocampal NSCs. As a result, Derlin-1-deficient mice exhibit phenotypes of increased seizure susceptibility and cognitive dysfunction. Reduced Stat5b expression is responsible for adult neurogenesis defects in Derlin-1-deficient NSCs. Inhibition of histone deacetylase activity effectively induces Stat5b expression and restores abnormal adult neurogenesis, resulting in improved seizure susceptibility and cognitive dysfunction in Derlin-1-deficient mice. Our findings indicate that the Derlin-1-Stat5b axis is indispensable for the homeostasis of adult hippocampal neurogenesis.
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Etomoxir suppresses the expression of PPARgamma2 and inhibits the thermogenic gene induction of brown adipocytes through pathways other than β-oxidation inhibition. Reviewed
Shimura H, Yamamoto S, Shiiba I, Oikawa M, Uchinomiya S, Ojida A, Yanagi S, Kadowaki H, Nishitoh H, Fukuda T, Nagashima S, Yamaguchi T
Journal of biochemistry 2024.12
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Sugiyama T., Murao N., Kadowaki H., Nishitoh H.
Scientific Reports 12 ( 1 ) 21840 2022.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
There are no available therapies targeting the underlying molecular mechanisms of neurodegenerative diseases. Although chaperone therapies that alleviate endoplasmic reticulum (ER) stress recently showed promise in the treatment of neurodegenerative diseases, the detailed mechanisms remain unclear. We previously reported that mice with central nervous system-specific deletion of Derlin-1, which encodes an essential component for ER quality control, are useful as models of neurodegenerative diseases such as spinocerebellar degeneration. Cholesterol biosynthesis is essential for brain development, and its disruption inhibits neurite outgrowth, causing brain atrophy. In this study, we report a novel mechanism by which chemical chaperones ameliorate brain atrophy and motor dysfunction. ER stress was induced in the cerebella of Derlin-1 deficiency mice, whereas the administration of a chemical chaperone did not alleviate ER stress. However, chemical chaperone treatment ameliorated cholesterol biosynthesis impairment through SREBP-2 activation and simultaneously relieved brain atrophy and motor dysfunction. Altogether, these findings demonstrate that ER stress may not be the target of action of chaperone therapies and that chemical chaperone-mediated improvement of brain cholesterol biosynthesis is a promising novel therapeutic strategy for neurodegenerative diseases.
Books 【 display / non-display 】
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実験医学別冊「疾患研究につながる オルガネラ実験必携プロトコール」小胞体関連分解ERADの解析方法
門脇寿枝（ Role： Joint author）
羊土社 2024.11
Book type：Scholarly book
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褐色脂肪組織における小胞体-ミトコンドリア間クロストークシグナルを介した熱産生
門脇寿枝、西頭英起（ Role： Joint author）
公益社団法人日本生化学会 2022.2
Language：Japanese Book type：Scholarly book
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アポトーシス. 「キーワード：蛋白質の一生」
門脇寿枝, 西頭英起（ Role： Joint author）
共立出版 2008.6
Language：Japanese Book type：Scholarly book
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異常タンパク質が発信する神経細胞死シグナル伝達
門脇寿枝, 西頭英起, 一條秀憲（ Role： Joint author）
実験医学 2006.6
Language：Japanese Book type：Scholarly book
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アミロイドβ誘導性神経細胞死の分子メカニズム
門脇寿枝, 西頭英起（ Role： Joint author）
Cognition and Dementia 2004.10
Language：Japanese Book type：Scholarly book
MISC 【 display / non-display 】
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Signaling Pathways from the Endoplasmic Reticulum and their Role in Diseases.
Kadowaki H., Nishitoh H.
Genes 4 ( 3 ) 306 - 333 2013.7
Language：English Publishing type：Article, review, commentary, editorial, etc. (scientific journal) Publisher： MDPI AG
DOI： 10.3390/genes4030306
Presentations 【 display / non-display 】
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Molecular mechanism of ER stress-dependent co-translational protein degradation Invited International conference
Hisae Kadowaki
AMED International Symposium “Proteostasis in Biology and Medicine” 2025.8.27
Event date： 2025.8.26 - 2025.8.29
Language：English Presentation type：Symposium, workshop panel (nominated)
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小胞体ストレス応答における翻訳時分解を介したタンパク質品質管理機構
門脇寿枝
第19回日本臨床ストレス応答学会 2025.11.15
Event date： 2025.11.14 - 2025.11.15
Presentation type：Oral presentation (general)
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小胞体ストレス依存的翻訳時分解によるタンパク質品質管理機構 Invited
門脇寿枝
令和7年度生化学会九州支部例会 2025.6.13
Event date： 2025.6.13 - 2025.6.14
Presentation type：Symposium, workshop panel (nominated)
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Molecular mechanism of stress-dependent co-translational protein degradation on the ER membrane International conference
Hisae Kadowaki, Hideki Nishitoh
EMBO workshop “Protein quality control: From molecular mechanisms to aging and disease”
Event date： 2025.5.18 - 2025.5.23
Language：English Presentation type：Poster presentation
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Molecular mechanism of stress-dependent co-translational degradation on the ER membrane Invited
Hisae Kadowaki
Ribosome meeting 2024 in Japan
Event date： 2024.12.2 - 2024.12.4
Presentation type：Oral presentation (invited, special)
Awards 【 display / non-display 】
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宮崎大学女性研究者奨励賞
2017.3 宮崎大学
門脇寿枝
Country：Japan
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第39回日本分子生物学会年会優秀ポスター賞
2016.11 日本分子生物学会
門脇寿枝
Award type：Award from Japanese society, conference, symposium, etc. Country：Japan
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第11回小胞体ストレス研究会ポスター大賞
2016.10 小胞体ストレス研究会
門脇寿枝
Award type：Award from Japanese society, conference, symposium, etc. Country：Japan
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若手研究奨励賞
2012.11 臨床ストレス応答学会
門脇寿枝
Award type：Award from Japanese society, conference, symposium, etc. Country：Japan
Grant-in-Aid for Scientific Research 【 display / non-display 】
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ストレス依存的な小胞体タンパク質の運命変更の法則
Grant number：25K10202 2025.04 - 2028.03
基盤研究(C)
Authorship：Principal investigator
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ストレス依存的な小胞体タンパク質の運命変更の法則
Grant number：25K10202 2025.04 - 2028.03
独立行政法人日本学術振興会 科学研究費基金 基盤研究(C)
Authorship：Principal investigator
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病態脳における小胞体プロテオスタシス破綻によるコレステロール合成不全と脳萎縮
Grant number：22H02954 2022.04 - 2025.03
基盤研究(B)
Authorship：Coinvestigator(s)
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小胞体ストレスにおける予防的品質管理の分子機構の解明
Grant number：21K06175 2021.04 - 2024.03
独立行政法人日本学術振興会 科学研究費補助金 基盤研究(C)
Authorship：Principal investigator
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小胞体ストレスによる新規合成タンパク質の分解機構の解明
Grant number：18K06222 2018.04 - 2021.03
科学研究費補助金 基盤研究(C)
Authorship：Principal investigator
Other research activities 【 display / non-display 】
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小胞体膜上での翻訳制御に関与する分子の構造解析
2025.04 - 2026.03
九州大学生体防御医学研究所「共同利用・共同研究」
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小胞体ストレス誘導性の翻訳と共役したタンパク質分解の分子機構の解明
2025.04 - 2026.03
徳島大学先端酵素学研究所「共同利用・共同研究」