Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 308; no. 4; pp. L344 - L357
• Main Authors: Liu, Fei, Lagares, David, Choi, Kyoung Moo, Stopfer, Lauren, Marinković, Aleksandar, Vrbanac, Vladimir, Probst, Clemens K., Hiemer, Samantha E., Sisson, Thomas H., Horowitz, Jeffrey C., Rosas, Ivan O., Fredenburgh, Laura E., Feghali-Bostwick, Carol, Varelas, Xaralabos, Tager, Andrew M., Tschumperlin, Daniel J.
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 15.02.2015
• Series: Translational Research in Acute Lung Injury and Pulmonary Fibrosis
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Binding sites; Biosynthesis; Call for Papers; Cell Cycle Proteins; Cellular biology; Drosophila; Female; Fibroblasts - metabolism; Fibroblasts - pathology; Gene Knockdown Techniques; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Lung - metabolism; Lung - pathology; Male; Mechanotransduction, Cellular - genetics; Mice; Mice, Inbred NOD; Mutation; NIH 3T3 Cells; Pathology; Phosphoproteins - genetics; Phosphoproteins - metabolism; Physiology; Plasminogen Activator Inhibitor 1 - biosynthesis; Plasminogen Activator Inhibitor 1 - genetics; Protein expression; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Serpin E2 - biosynthesis; Serpin E2 - genetics; Signal transduction; Trans-Activators; Transcription Factors; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; idiopathic pulmonary fibrosis; Hippo; mechanotransduction; extracellular matrix; plasminogen activator inhibitor 1
• ISSN: 1040-0605; 1522-1504; 1522-1504
• DOI: 10.1152/ajplung.00300.2014

Pathological fibrosis is driven by a feedback loop in which the fibrotic extracellular matrix is both a cause and consequence of fibroblast activation. However, the molecular mechanisms underlying this process remain poorly understood. Here we identify yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. YAP and TAZ are prominently expressed in fibrotic but not healthy lung tissue, with particularly pronounced nuclear expression of TAZ in spindle-shaped fibroblastic cells. In culture, both YAP and TAZ accumulate in the nuclei of fibroblasts grown on pathologically stiff matrices but not physiologically compliant matrices. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1, which is regulated by matrix stiffness independent of transforming growth factor-β signaling. Immortalized fibroblasts conditionally expressing active YAP or TAZ mutant proteins overcome soft matrix limitations on growth and promote fibrosis when adoptively transferred to the murine lung, demonstrating the ability of fibroblast YAP/TAZ activation to drive a profibrotic response in vivo. Together, these results identify YAP and TAZ as mechanoactivated coordinators of the matrix-driven feedback loop that amplifies and sustains fibrosis.