title: Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis.
abstract: 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.
authors.affiliation: Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts;
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Pulmonary and Critical Care Unit and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, Massachusetts;
authors.forename: David
authors.initials: D
authors.lastname: Lagares
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota;
authors.forename: Kyoung Moo
authors.initials: KM
authors.lastname: Choi
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota;
authors.forename: Lauren
authors.initials: L
authors.lastname: Stopfer
authors.affiliation: Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts;
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Marinković
authors.affiliation: Pulmonary and Critical Care Unit and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, Massachusetts;
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vrbanac
authors.affiliation: Pulmonary and Critical Care Unit and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, Massachusetts;
authors.forename: Clemens K
authors.initials: CK
authors.lastname: Probst
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts;
authors.forename: Samantha E
authors.initials: SE
authors.lastname: Hiemer
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan;
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Sisson
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan;
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Horowitz
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Rosas
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Laura E
authors.initials: LE
authors.lastname: Fredenburgh
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Carol
authors.initials: C
authors.lastname: Feghali-Bostwick
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts;
authors.forename: Xaralabos
authors.initials: X
authors.lastname: Varelas
authors.affiliation: Pulmonary and Critical Care Unit and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, Massachusetts;
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tager
authors.affiliation: Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; tschumperlin.daniel@mayo.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Tschumperlin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D040542:Mechanotransduction, Cellular / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D009154:Mutation; D041681:NIH 3T3 Cells; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058258:Serpin E2 / Q000096:biosynthesis / Q000235:genetics; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D016212:Transforming Growth Factor beta; C551991:WWTR1 protein, human; C517794:Wwtr1 protein, mouse; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse
keywords: Hippo; extracellular matrix; idiopathic pulmonary fibrosis; mechanotransduction; plasminogen activator inhibitor 1