Cysteine S-Glutathionylation Promotes Stability and Activation of the Hippo Downstream Effector Transcriptional Co-activator with PDZ-binding Motif (TAZ)

J Biol Chem. 2016 May 27;291(22):11596-607. doi: 10.1074/jbc.M115.712539. Epub 2016 Apr 5.

Abstract

Transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP) are critical transcriptional co-activators downstream of the Hippo pathway involved in the regulation of organ size, tissue regeneration, proliferation, and apoptosis. Recent studies suggested common and distinct functions of TAZ and YAP and their diverse impact under several pathological conditions. Here we report differential regulation of TAZ and YAP in response to oxidative stress. H2O2 exposure leads to increased stability and activation of TAZ but not of YAP. H2O2 induces reversible S-glutathionylation at conserved cysteine residues within TAZ. We further demonstrate that TAZ S-glutathionylation is critical for reactive oxygen species (ROS)-mediated, TAZ-dependent TEA domain transcription factor (TEAD) trans-activation. Lysophosphatidic acid, a physiological activator of YAP and TAZ, induces ROS elevation and, subsequently, TAZ S-glutathionylation, which promotes TAZ-mediated target gene expression. TAZ expression is essential for renal homeostasis in mice, and we identify basal TAZ S-glutathionylation in murine kidney lysates, which is elevated during ischemia/reperfusion injury in vivo This induced nuclear localization of TAZ and increased expression of connective tissue growth factor. These results describe a novel mechanism by which ROS sustains total cellular levels of TAZ. This preferential regulation suggests TAZ to be a redox sensor of the Hippo pathway.

Keywords: Hippo pathway; S-glutathionylation; Yes-associated protein (YAP); connective tissue growth factor (CTGF); oxidative stress; reactive oxygen species (ROS); transcriptional co-activator with PDZ-binding motif (TAZ).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • Cell Cycle Proteins
  • Cells, Cultured
  • Connective Tissue Growth Factor / genetics
  • Connective Tissue Growth Factor / metabolism
  • Cysteine / chemistry
  • Cysteine / metabolism*
  • Glutathione / chemistry
  • Glutathione / metabolism*
  • Hydrogen Peroxide / pharmacology
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oxidants / pharmacology
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein Processing, Post-Translational
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reperfusion Injury / drug therapy
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / pathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Amino Acid
  • Signal Transduction / drug effects
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Oxidants
  • Phosphoproteins
  • RNA, Messenger
  • Trans-Activators
  • Transcription Factors
  • WWTR1 protein, human
  • YY1AP1 protein, human
  • Connective Tissue Growth Factor
  • Hydrogen Peroxide
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases
  • Glutathione
  • Cysteine