Tianzhou Zhang1, Xiaolin He1, Lauren Caldwell2, Santosh Kumar Goru1, Luisa Ulloa Severino1, Monica F. Tolosa1, Paraish S. Misra1, Caitríona M. McEvoy1, Tania Christova3, Yong Liu4, Cassandra Atin1, Johnny Zhang1, Catherine Hu1, Noah Vukosa1, Xiaolan Chen1, Adriana Krizova5, Anish Kirpalani6, Alex Gregorieff2, Ruoyu Ni2, Kin Chan2, Mandeep Gill3, Liliana Attisano3, Jeffrey L. Wrana2, Darren A. Yuen1
1Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital (Unity Health Toronto) and Department of Medicine, University of Toronto, Toronto, Ontario M5B 1T8, Canada.
2Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital and Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1X5, Canada.
3Donnelly Centre and Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
4Ontario Institute of Cancer Research, Toronto, Ontario M5G OA3, Canada.
5Department of Laboratory Medicine and Pathobiology, School of Graduate Studies, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
6Department of Medical Imaging, St. Michael’s Hospital (Unity Health Toronto) and University of Toronto, Toronto, Ontario M5B 1W8, Canada.
Tóm tắt
Fibrosis is a central pathway that drives progression of multiple chronic diseases, yet few safe and effective clinical antifibrotic therapies exist. In most fibrotic disorders, transforming growth factor–β (TGF-β)–driven scarring is an important pathologic feature and a key contributor to disease progression. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two closely related transcription cofactors that are important for coordinating fibrogenesis after organ injury, but how they are activated in response to tissue injury has, so far, remained unclear. Here, we describe NUAK family kinase 1 (NUAK1) as a TGF-β–inducible profibrotic kinase that is up-regulated in multiple fibrotic organs in mice and humans. Mechanistically, we show that TGF-β induces a rapid increase in NUAK1 in fibroblasts. NUAK1, in turn, can promote profibrotic YAP and TGF-β/SMAD signaling, ultimately leading to organ scarring. Moreover, activated YAP and TAZ can induce further NUAK1 expression, creating a profibrotic positive feedback loop that enables persistent fibrosis. Using mouse models of kidney, lung, and liver fibrosis, we demonstrate that this fibrogenic signaling loop can be interrupted via fibroblast-specific loss of NUAK1 expression, leading to marked attenuation of fibrosis. Pharmacologic NUAK1 inhibition also reduced scarring, either when initiated immediately after injury or when initiated after fibrosis was already established. Together, our data suggest that NUAK1 plays a critical, previously unrecognized role in fibrogenesis and represents an attractive target for strategies that aim to slow fibrotic disease progression.
