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

Kyungsun 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 journalArticle

15 Citations (Scopus)

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. CONCLUSION-: 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)321-329
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume33
Issue number2
DOIs
StatePublished - Feb 1 2013

Fingerprint

Ubiquitin-Protein Ligases
Ubiquitin
Mitogen-Activated Protein Kinases
Protein Kinases
Phosphorylation
Inflammation
Sumoylation
Proteins
Kruppel-Like Transcription Factors
Ligases
Nitric Oxide Synthase
Replication Protein C
STAT Transcription Factors
Leukocyte Rolling
STAT1 Transcription Factor
Mutant Proteins
Protein Kinase Inhibitors
Microvessels
Adenoviridae
Anti-Inflammatory Agents

Keywords

  • MAPK-activated protein kinase-2
  • endothelial inflammation
  • nuclear factor-κB transrepression
  • protein inhibitor of activated signal transducer and activator of transcription-1
  • vascular biology

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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. / Heo, Kyungsun; Chang, Eugene; Takei, Yuichiro; Le, Nhat Tu; Woo, Chang Hoon; Sullivan, Mark A.; Morrell, Craig; Fujiwara, Keigi; Abe, Jun-ichi.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 33, No. 2, 01.02.2013, p. 321-329.

Research output: Contribution to journalArticle

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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. CONCLUSION-: 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.",
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AU - Chang, Eugene

AU - Takei, Yuichiro

AU - Le, Nhat Tu

AU - Woo, Chang Hoon

AU - Sullivan, Mark A.

AU - Morrell, Craig

AU - Fujiwara, Keigi

AU - Abe, Jun-ichi

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