Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis

Am J Physiol Lung Cell Mol Physiol. 2015 Feb 15;308(4):L344-57. doi: 10.1152/ajplung.00300.2014. Epub 2014 Dec 12.

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.

Keywords: Hippo; extracellular matrix; idiopathic pulmonary fibrosis; mechanotransduction; plasminogen activator inhibitor 1.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Cycle Proteins
  • 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
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Plasminogen Activator Inhibitor 1 / biosynthesis
  • Plasminogen Activator Inhibitor 1 / genetics
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / pathology
  • Serpin E2 / biosynthesis
  • Serpin E2 / genetics
  • Transcription Factors
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Plasminogen Activator Inhibitor 1
  • SERPINE1 protein, human
  • Serpin E2
  • Serpine2 protein, mouse
  • Transcription Factors
  • Transforming Growth Factor beta
  • WWTR1 protein, human
  • Wwtr1 protein, mouse
  • YAP1 (Yes-associated) protein, human
  • Yap protein, mouse