| 1. |
Yuma Horii, Shoichi Matsuda, Chikashi Toyota, Takumi Morinaga, Takeo Nakaya, Soken Tsuchiya, Masaki Ohmuraya, Takanori Hironaka, Ryo Yoshiki, Kotaro Kasai, Yuto Yamauchi, Noburo Takizawa, Akiomi Nagasaka, Akira Tanaka, Hidetaka Kosako, and Michio Nakaya, VGLL3 is a mechanosensitive protein that promotes cardiac fibrosis through liquid-liquid phase separation., Nat. Commun., 14, 1, 550, 2023.02, Myofibroblasts cause tissue fibrosis by producing extracellular matrix proteins,
such as collagens. Humoral factors like TGF-β, and matrix stiffness are
important for collagen production by myofibroblasts. However, themolecular
mechanisms regulating their ability to produce collagen remain poorly characterised.
Here, we show that vestigial-like family member 3 (VGLL3) is specifically
expressed in myofibroblasts from mouse and human fibrotic hearts
and promotes collagen production. Further, substrate stiffness triggers VGLL3
translocation into the nucleus through the integrin β1-Rho-actin pathway. In
the nucleus, VGLL3 undergoes liquid-liquid phase separation via its lowcomplexity
domain and is incorporated into non-paraspeckle NONO condensates
containing EWS RNA-binding protein 1 (EWSR1). VGLL3 binds EWSR1
and suppresses miR-29b, which targets collagen mRNA. Consistently, cardiac
fibrosis aftermyocardial infarction is significantly attenuated in Vgll3-deficient
mice, with increased miR-29b expression. Overall, our results reveal an
unrecognised VGLL3-mediated pathway that controlsmyofibroblasts’ collagen
production, representing a novel therapeutic target for tissue fibrosis.. |
| 2. |
仲矢 道雄, 渡健治, 田島充, TAKEO NAKAYA, 松田翔一, 西原弘朗, 山口裕嗣, 橋本明子, 西田光甫, AKIOMI NAGASAKA, 堀井雄馬, 小野達貴, Gentaro Iribe, Ryuji Inoue, TSUDA MAKOTO, Kazuhide Inoue, Akira Tanaka, Masahiko Kuroda, Shigekazu Nagata, Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction, JOURNAL OF CLINICAL INVESTIGATION, 10.1172/JCI83822, 127, 1, 383-401, 2017.01, 心筋梗塞時に心臓の線維化を担うのみと考えられていた筋線維芽細胞が、心筋梗塞時の死細胞を貪食する機能を持つことを世界に先駆けて見出した。そして、その貪食がMFG-E8という分子を介して行われていることを見出した。さらに、そのMFG-E8タンパク質を心筋梗塞後の心臓に投与すると、心筋梗塞後の死細胞の貪食が亢進し、心筋梗塞後の病態が改善することを見出した。. |
| 3. |
Nakaya Michio, 渡健治, Motohiro Nishida, Kyeong-Man Kim, Hitoshi Kurose, β-arrestin2 in infiltrated macrophages inhibits excessive inflammation after myocardial infarction, PLoS One, 8(7), e68351, 2013.05. |
| 4. |
Nakaya Michio, Mitsuru Tajima, Hidetaka Kosako, Takeo Nakaya, Hiroaki Nishihara, Mina Ohba, Shiori Komiya, Naoki Tani, Motohiro Nishida, Hisaaki Taniguchi, Yoji Sato, Mitsuru Matsumoto, TSUDA MAKOTO, Masahiko Kuroda, Kazuhide Inoue, Hitoshi Kurose, GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance., Nat. Commun. , 287, 1532, 2013.02, 生体内で死んだ細胞はマクロファージなどの貪食細胞によって積極的に取り込まれ、消化されて無くなってしまいます。この速やかな貪食は、死んだ細胞からの内容物の流出を防ぐ等、生体の恒常性を維持する上で極めて重要な役割を担っています。九州大学大学院薬学研究院薬効安全性学分野の黒瀬等教授と仲矢道雄准教授を中心とする研究グループ（九州大学大学院薬学研究院薬理学分野の井上和秀主幹教授、東京医科大学分子病理学講座の黒田雅彦主任教授、徳島大学疾患酵素学センター疾患プロテオミクス研究部門の小迫英尊准教授ら）は、このアポトーシス細胞の貪食にGRK6というタンパク質が関与している事を世界で初めて見出しました。GRK6を欠損したマウスは貪食能の低下が原因で全身性エリテマトーデスや鉄過剰症様の症状を呈しました。従って、GRK6はこれら疾患の治療に関する新たなターゲット分子となることが期待されます。
本研究成果は、平成25年2月26日（火）（現地時間）に英国科学雑誌 「Nature Communications」オンライン版に掲載されました。. |
| 5. |
Nakaya Michio, Chikura Satsuki, Watari Kenji, Mizuno Natsumi, Mochinaga Koji, Supachoke Mangmool, Koyanagi Satoru, shigehiro ohdo, Sato Yoji, Ide Tomomi, Motohiro Nishida, Hitoshi Kurose, Induction of cardiac fibrosis by β-blocker in G protein-independent but GRK5/β-arrestin2-dependent signaling pathways. , J. Biol. Chem. , 287, 35669-35677, 2012.08. |
| 6. |
Nishida M, Sato Y, Uemura A, Narita Y, Toazaki-Saitoh H, Nakaya M, Ide T, Suzuki K, Inoue K, Nagao T, Kurose H., P2Y6 receptor-Galpha12/13 signalling in cardiomyocytes triggers pressure overload-induced cardiac fibrosis., EMBO Journal, 27(23) 3104-3115., 2008.12. |
| 7. |
Michio Nakaya, Masahiro Kitano, Michiyuki Matsuda, Shigekazu Nagata, Spatiotemporal regulation of Rac1 to control actin patch for engulfment of apoptotic cells, Proceedings of the National Academy of Sciences, 105 (27) 9198-9203, 2008.07. |
| 8. |
Masahiro Kitano, Michio Nakaya, Takeshi Nakamura, Shigekazu Nagata, Michiyuki Matsuda, Imaging of Rab5 activity identifies essential regulators for phagosome maturation, Nature, 453 (7192) 241-245, 2008.05. |
| 9. |
Nakaya M, Tanaka M, Okabe Y, Hanayama R, Nagata S, Opposite effects of Rho family GTPases on engulfment of apoptotic cells by macrophages., Journal of Biological Chemistry, 281(13) 8836-8842, 2006.03. |
