VGLL3 is a mechanosensitive protein that promotes cardiac fibrosis through liquid–liquid phase separation

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 ()
Additional contact information
Yuma Horii: Kyushu University
Shoichi Matsuda: Kyushu University
Chikashi Toyota: Kyushu University
Takumi Morinaga: Kyushu University
Takeo Nakaya: Jichi Medical University
Soken Tsuchiya: Kumamoto University
Masaki Ohmuraya: Hyogo College of Medicine
Takanori Hironaka: Kyushu University
Ryo Yoshiki: Kyushu University
Kotaro Kasai: Kyushu University
Yuto Yamauchi: Kyushu University
Noburo Takizawa: Kyushu University
Akiomi Nagasaka: Kyushu University
Akira Tanaka: Jichi Medical University
Hidetaka Kosako: Tokushima University
Michio Nakaya: Kyushu University

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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, the molecular 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 low-complexity 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 after myocardial infarction is significantly attenuated in Vgll3-deficient mice, with increased miR-29b expression. Overall, our results reveal an unrecognised VGLL3-mediated pathway that controls myofibroblasts’ collagen production, representing a novel therapeutic target for tissue fibrosis.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-36189-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36189-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-36189-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().