Corrected and Republished from: The COP9 Signalosome Interacts with and Regulates Interferon Regulatory Factor 5 Protein Stability

ABSTRACT The transcription factor interferon regulatory factor 5 (IRF5) exerts crucial functions in the regulation of host immunity against extracellular pathogens, DNA damage-induced apoptosis, death receptor signaling, and macrophage polarization. Tight regulation of IRF5 is thus warranted for an efficient response to extracellular stressors and for limiting autoimmune and inflammatory responses. Here we report that the COP9 signalosome (CSN), a general modulator of diverse cellular and developmental processes, associates constitutively with IRF5 and promotes its protein stability. The constitutive CSN/IRF5 interaction was identified using proteomics and confirmed by endogenous immunoprecipitations. The CSN/IRF5 interaction occurred on the carboxyl and amino termini of IRF5; a single internal deletion (Δ455-466) was found to significantly reduce IRF5 protein stability. CSN3 was identified as a direct interacting partner of IRF5, and knockdown of this subunit with small interfering RNAs (siRNAs) resulted in enhanced degradation. Degradation was further augmented by knockdown of CSN1 and CSN3 together. The ubiquitin E1 inhibitor UBEI-41 or the proteasome inhibitor MG132 prevented IRF5 degradation, supporting that its stability is regulated by the ubiquitin-proteasome system. Importantly, activation of IRF5 by the death receptor ligand tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) resulted in enhanced degradation via loss of the CSN/IRF5 interaction. This study defines the CSN as a new interacting partner of IRF5 that controls its stability.

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The COP9 Signalosome Interacts with and Regulates Interferon Regulatory Factor 5 Protein Stability

Molecular and Cellular Biology ◽

10.1128/mcb.00802-12 ◽

2012 ◽

Vol 33 (6) ◽

pp. 1124-1138 ◽

Cited By ~ 15

Author(s):

Justyna Korczeniewska ◽

Betsy J. Barnes

Keyword(s):

Protein Stability ◽

Inflammatory Responses ◽

Macrophage Polarization ◽

Death Receptor ◽

Interferon Regulatory Factor ◽

Cop9 Signalosome ◽

Small Interfering Rnas ◽

Regulatory Factor ◽

Interferon Regulatory Factor 5 ◽

Enhanced Degradation

The transcription factor interferon regulatory factor 5 (IRF5) exerts crucial functions in the regulation of host immunity against extracellular pathogens, DNA damage-induced apoptosis, death receptor signaling, and macrophage polarization. Tight regulation of IRF5 is thus warranted for an efficient response toward extracellular stressors and for limiting autoimmune and inflammatory responses. Here we report that the COP9 signalosome (CSN), a general modulator of diverse cellular and developmental processes, associates constitutively with IRF5 and promotes its protein stability. The constitutive CSN/IRF5 interaction was identified using proteomics and confirmed by endogenous immunoprecipitations. The CSN/IRF5 interaction occurred on the carboxyl and amino termini of IRF5; a single internal deletion from amino acids 455 to 466 (Δ455-466) was found to significantly reduce IRF5 protein stability. CSN subunit 3 (CSN3) was identified as a direct interacting partner of IRF5, and knockdown of this subunit with small interfering RNAs resulted in enhanced degradation. Degradation was further augmented by knockdown of CSN1 and CSN3 together. The ubiquitin E1 inhibitor UBEI-41 or the proteasome inhibitor MG132 prevented IRF5 degradation, supporting the idea that its stability is regulated by the ubiquitin-proteasome system. Importantly, activation of IRF5 by the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resulted in enhanced degradation via loss of the CSN/IRF5 interaction. This study defines CSN to be a new interacting partner of IRF5 that controls its stability.

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Retraction for Korczeniewska and Barnes, “The COP9 Signalosome Interacts with and Regulates Interferon Regulatory Factor 5 Protein Stability”

Molecular and Cellular Biology ◽

10.1128/mcb.00477-17 ◽

2017 ◽

Vol 37 (24) ◽

Author(s):

Justyna Korczeniewska ◽

Betsy J. Barnes

Keyword(s):

Protein Stability ◽

Interferon Regulatory Factor ◽

Cop9 Signalosome ◽

Regulatory Factor ◽

Interferon Regulatory Factor 5

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Interferon Regulatory Factor 5 Mediates Lipopolysaccharide-Induced Neuroinflammation

Frontiers in Immunology ◽

10.3389/fimmu.2020.600479 ◽

2020 ◽

Vol 11 ◽

Author(s):

Ziqi Fan ◽

Shuai Zhao ◽

Yueli Zhu ◽

Zheyu Li ◽

Zhirong Liu ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Interferon Regulatory Factor ◽

Microglial Cells ◽

Regulatory Factor ◽

Down Regulation ◽

Interferon Regulatory Factor 5 ◽

Bv2 Microglial Cells ◽

Lps Treatment ◽

Pro Inflammatory Cytokines

BackgroundActivated microglia play a vital role in neuroinflammation in the central nervous system (CNS), which is associated with the pathogenesis and the progression of neurological diseases. Interferon regulatory factor 5 (IRF5) has been well established participating in inflammatory responses and is highly expressed in M1 macrophage in the periphery, the role of which in the CNS remains elusive.MethodsLipopolysaccharide (LPS) was employed to induce neuroinflammation. Down-regulation of IRF5 in C57/BL6 mice and BV2 microglial cells were achieved by IRF5 siRNA transfection. The levels of pro-inflammatory cytokines were evaluated by ELISA and quantitative real-time PCR. The expression levels of IRF5 were examined by immunofluorescence and Western blot.ResultsLPS induced significantly elevated expression of IRF5 in mouse brain, which co-localized with CD11b-positive microglia. Down-regulation of IRF5 quenched the pro-inflammatory responses. The levels of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were up-regulated at 4 h after LPS treatment, which were significantly down-regulated with the knockdown of IRF5. LPS-induced pro-inflammatory responses were transient, which were comparable to control group at 24 h after LPS treatment. However, LPS did not up-regulate the expression of IRF5 in BV2 microglial cells, indicating that LPS-induced inflammation in BV2 cells does not involve IRF5 signaling.ConclusionsIRF5 mediates the inflammatory responses in the CNS, which might serve as a therapeutic target for CNS inflammatory diseases. LPS-induced inflammation does not involve IRF5 signaling in BV2 microglia.

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Interferon Regulatory Factor 5 Mediates Lipopolysaccharide Induced Neuroinflammation

10.21203/rs.3.rs-23387/v1 ◽

2020 ◽

Author(s):

Ziqi Fan ◽

Shuai Zhao ◽

Yueli Zhu ◽

Zheyu Li ◽

Zhirong Liu ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Interferon Regulatory Factor ◽

Microglial Cells ◽

Regulatory Factor ◽

Down Regulation ◽

Interferon Regulatory Factor 5 ◽

Bv2 Microglial Cells ◽

Lps Treatment ◽

Pro Inflammatory Cytokines

Abstract Background Activated microglia plays a vital role in neuroinflammation in central nervous system (CNS), which is associated with the pathogenesis and the progression of neurological diseases. Interferon regulatory factor 5 (IRF5) has been well established participating in inflammatory responses and is highly expressed in M1 macrophage in periphery, the role of which in the CNS remains elusive. Methods Lipopolysaccharide (LPS) was employed to induce neuroinflammation. Down-regulation of IRF5 in C57/BL6 mice and BV2 microglial cells were achieved by IRF5 siRNA transfection. The levels of pro-inflammatory cytokines were evaluated by ELISA and quantitative real-time PCR. The expression levels of IRF5 were examined by immnunofluorescence and Western blot. Results LPS induced significantly elevated expression of IRF5 in mouse brain, which co-localized with CD11b positive microglia. Down-regulation of IRF5 quenched the pro-inflammatory responses. The levels of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 were up-regulated at 4 h after LPS treatment, which were significantly down-regulated with the knockdown of IRF5. LPS-induced pro-inflammatory responses were transient, which returned to basal level at 24 h after LPS treatment. However, LPS did not up-regulate the expression of IRF5 in BV2 microglial cells, indicating that LPS-induced inflammation in BV2 cells does not involve IRF5 signaling. Conclusions IRF5 mediates the inflammatory responses in the CNS, which might serve as a therapeutic target for CNS inflammatory diseases. LPS-induced inflammation does not involve IRF5 signaling in BV2 microglia.

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