Phosphorylation of protein inhibitor of activated STAT1 (PIAS1) by MAPK-activated protein kinase-2 inhibits endothelial inflammation via increasing both PIAS1 transrepression and SUMO E3 ligase activity

Kyung-Sun Heo, Eugene Chang, Yuichiro Takei, Nhat-Tu Le, Chang-Hoon Woo, Mark A Sullivan, Craig Morrell, Keigi Fujiwara, Jun-ichi Abe

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

OBJECTIVE: Protein inhibitor of activated signal transducer and activator of transcription-1 (PIAS1) is known to function as small ubiquitin-like modifier (SUMO) E3 ligase as well as transrepressor. The aim of the study is to elucidate the regulatory mechanisms for these 2 different functions, especially with respect to endothelial inflammation.

METHODS AND RESULTS: The mitogen-activated protein kinase (MAPK)-activated protein kinase-2 is a proinflammatory kinase and phosphorylates PIAS1 at the Ser522 residue. Activation of MAPK-activated protein kinase-2 enhances p53-SUMOylation, but a PIAS1 phosphorylation mutant, PIAS1-S522A, abolished this p53-SUMOylation, suggesting a critical role for PIAS1-S522 phosphorylation in its SUMO ligase activity. Because nuclear p53 can inhibit Kruppel-like factor 2 promoter activity, we investigated the roles for PIAS1 phosphorylation and p53-SUMOylation in the Kruppel-like factor 2 and endothelial NO synthase expression. Both MAPK-activated protein kinase-2 and PIAS1 overexpression increased Kruppel-like factor 2 promoter activity and endothelial NO synthase expression, which were inhibited by expressing a p53-SUMOylation defective mutant, p53-K386R, and PIAS1-S522A. PIAS1-S522A also abolished the anti-inflammatory effect of wild-type PIAS1 in vitro and also in vivo, which was examined by leukocyte rolling in microvessels of skin grafts transduced by adenovirus encoding PIAS1-WT or - S522A mutant.

CONCLUSIONS: Our study has identified a novel negative feedback regulatory pathway through which MAPK-activated protein kinase-2 limits endothelial inflammation via the PIAS1 S522 phosphorylation-mediated increase in PIAS1 transrepression and SUMO ligase activity.

Original languageEnglish (US)
Pages (from-to)321-9
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume33
Issue number2
DOIs
StatePublished - Feb 2013
Externally publishedYes

Keywords

  • Animals
  • Cells, Cultured
  • Endothelial Cells
  • Enzyme Activation
  • Gene Expression Regulation
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Inflammation
  • Inflammation Mediators
  • Intracellular Signaling Peptides and Proteins
  • Kruppel-Like Transcription Factors
  • Leukocyte Rolling
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B
  • Nitric Oxide Synthase Type III
  • Phosphorylation
  • Protein Inhibitors of Activated STAT
  • Protein-Serine-Threonine Kinases
  • RNA Interference
  • Skin
  • Skin Transplantation
  • Small Ubiquitin-Related Modifier Proteins
  • Sumoylation
  • Time Factors
  • Transfection
  • Transplantation, Autologous
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53
  • Ubiquitin-Protein Ligases
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

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