Differential SUMOylation of LXRα and LXRβ Mediates Transrepression of STAT1 Inflammatory Signaling in IFN-γ-Stimulated Brain Astrocytes

Lee, Jee Hoon; Park, Sang Myun; Kim, Ohn Soon; Lee, Chang Seok; Woo, Joo Hong; Park, Soo Jung; Joe, Eun-hye; Jou, Ilo

doi:10.1016/j.molcel.2009.07.021

Cited by 161Cytokine Signaling Pathways and Interactionsinterferon and immune responsesPeroxisome Proliferator-Activated Receptors

Differential SUMOylation of LXRα and LXRβ Mediates Transrepression of STAT1 Inflammatory Signaling in IFN-γ-Stimulated Brain Astrocytes

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Lee, Jee Hoon, Park, Sang Myun, Kim, Ohn Soon, Lee, Chang Seok, Woo, Joo Hong, Park, Soo Jung, Joe, Eun-hye, Jou, Ilo·2009·Molecular Cell

DOI 10.1016/j.molcel.2009.07.021

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Abstract

To unravel the roles of LXRs in inflammation and immunity, we examined the function of LXRs in development of IFN-gamma-mediated inflammation using cultured rat brain astrocytes. LXR ligands inhibit neither STAT1 phosphorylation nor STAT1 translocation to the nucleus but, rather, inhibit STAT1 binding to promoters and the expression of IRF1, TNFalpha, and IL-6, downstream effectors of STAT1 action. Immunoprecipitation data revealed that LXRbeta formed a trimer with PIAS1-pSTAT1, whereas LXRalpha formed a trimer with HDAC4-pSTAT1, mediated by direct ligand binding to the LXR proteins. In line with the fact that both PIAS1 and HDAC4 belong to the SUMO E3 ligase family, LXRbeta and LXRalpha were SUMO-conjugated by PIAS1 or HDAC4, respectively, and SUMOylation was blocked by transient transfection of appropriate individual siRNAs, reversing LXR-induced suppression of IRF1 and TNFalpha expression. Together, our data show that SUMOylation is required for the suppression of STAT1-dependent inflammatory responses by LXRs in IFN-gamma-stimulated brain astrocytes.

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HDAC4 belongs to the SUMO E3 ligase family and can directly SUMOylate IκBα, AR, LXRα, and MEF2.
“Additionally, HDAC4 belongs to the SUMO E3 ligase family and can directly SUMOylate IκBα, AR, LXRα, and MEF217–20.”
From An HDAC4-specific PROTAC degrader achieves radiation sensitization by enhancing ferroptosis in lung cancer (2026) · cites this paper as [19]
The Results report that HDAC4 acts as a SUMO E3 ligase and that LXRα was SUMOylated by HDAC4 in brain astrocytes, with in vitro assays providing further confirmation. Our copy does not report HDAC4 directly SUMOylating IκBα, AR, or MEF2; MEF2 appears in cited references, not as a substrate tested here. Page numbers are unavailable in the indexed copy. (LLM, conf=0.88)
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Background

Authors: Lee, J. H., Park, S. M., Kim, O. S., Lee, C. S., Woo, J. H., Park, S. J., Joe, E.-H., & Jou, I.
Affiliations: Ajou University (KR)
Corresponding author: Jou, Ilo
ORCID: Lee, Jee Hoon
Park, Sang Myun
Lee, Chang Seok
Woo, Joo Hong
Park, Soo Jung
Joe, Eun-hye
Jou, Ilo
Venue: Molecular Cell
Publisher: Elsevier BV
Published: 2009-09
Volume: 35
Issue: 6
Pages: 806-817
ISSN: 1097-2765 (ISSN-L)
DOI: 10.1016/j.molcel.2009.07.021
OpenAlex: W2081594562
Cited by: 161
References: 37
Citations by year: 2026: 5 · 2025: 7 · 2024: 6 · 2023: 6 · 2022: 2 · 2021: 9 · 2020: 9 · 2019: 4 · 2018: 8 · 2017: 12 · 2016: 13 · 2015: 15 · 2014: 10 · 2013: 20 · 2012: 8
FWCI: 5.79
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1415 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Molecular Cell (publishedVersion)
PubMed (publishedVersion)
Funders: Ministry of Science and Technology, Taiwan (R13-2003-019-01006)
Korea Science and Engineering Foundation
Topics: Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords: liver X receptor alpha, LXRβ, SUMOylation, STAT1, transrepression, interferon-gamma, brain astrocytes, PIAS1, HDAC4, SUMO E3 ligase, IRF1, TNF-α, interleukin-6, neuroinflammation, nuclear translocation
MeSH terms: Liver X Receptors, Animals, Animals, Newborn, Astrocytes, Binding Sites, Cells, Cultured, DNA-Binding Proteins, Histone Deacetylases, Inflammation, Interferon-gamma, Ligands, Phosphorylation, Promoter Regions, Genetic, Protein Processing, Post-Translational, Transfection, Tumor Necrosis Factor-alpha, Signal Transduction, Interleukin-6, Rats, Sprague-Dawley, Receptors, Cytoplasmic and Nuclear, Inflammation Mediators, Active Transport, Cell Nucleus, Small Ubiquitin-Related Modifier Proteins, RNA Interference, STAT1 Transcription Factor, Protein Inhibitors of Activated STAT, Interferon Regulatory Factor-1, Rats, Orphan Nuclear Receptors

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Differential SUMOylation of LXRα and LXRβ Mediates Transrepression of STAT1 Inflammatory Signaling in IFN-γ-Stimulated Brain Astrocytes

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