TBK1 regulates YAP/TAZ and fibrogenic fibroblast activation

Aja Aravamudhan, Andrew J. Haak, Kyoung Moo Choi, Jeffrey A. Meridew, Nunzia Caporarello, Dakota L. Jones, Qi Tan, Giovanni Ligresti, Daniel J. Tschumperlin

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Idiopathic pulmonary fibrosis (IPF) results in scarring of the lungs by excessive extracellular matrix (ECM) production. Resident fibroblasts are the major cell type involved in ECM deposition. The biochemical pathways that facilitate pathological fibroblast activation leading to aberrant ECM deposition are not fully understood. Tank binding protein kinase-1 (TBK1) is a kinase that regulates multiple signaling pathways and was recently identified as a candidate regulator of fibroblast activation in a large-scale small-interfering RNA (siRNA) screen. To determine the effect of TBK1 on fibroblast activation, TBK1 was inhibited pharmacologically (MRT-68601) and genetically (siRNA) in normal and IPF human lung fibroblasts. Reducing the activity or expression of TBK1 led to reduction in α-smooth muscle actin stress fiber levels by 40 - 60% and deposition of ECM components collagen I and fibronectin by 50% in TGF-β-stimulated normal and IPF fibroblasts. YAP and TAZ are homologous mechanoregulatory profibrotic transcription cofactors known to regulate fibroblast activation. TBK1 knockdown or inhibition decreased the total and nuclear protein levels of YAP/ TAZ. Additionally, low cell-cell contact and increased ECM substrate stiffness augmented the phosphorylation and activation of TBK1, consistent with cues that regulate YAP/TAZ. The action of TBK1 toward YAP/TAZ activation was independent of LATS1/2 and canonical downstream TBK1 signaling mediator IRF3 but dependent on proteasomal machinery of the cell. This study identifies TBK1 as a fibrogenic activator of human pulmonary fibroblasts, suggesting TBK1 may be a novel therapeutic target in pulmonary fibrosis.

Original languageEnglish (US)
Pages (from-to)L852-L863
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume318
Issue number5
DOIs
StatePublished - May 2020

Keywords

  • Extracellular matrix
  • Fibroblast
  • Fibrosis
  • Mechanosignaling
  • YAP/ TAZ

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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