Role of the IRF-1 enhancer domain in signalling polyubiquitination and degradation

Pion, Emmanuelle; Narayan, Vikram; Eckert, Mirjam; Ball, Kathryn L.

doi:10.1016/j.cellsig.2009.05.004

Cited by 27 publications

(45 citation statements)

References 34 publications

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“…Structure-function analysis has defined the enhancer domain as a key regulatory site involved in controlling IRF-1-dependent effects on gene expression and cell growth. Furthermore, we have defined the Mf1 domain as a distinct region of the enhancer that contains an LXXLL motif that is central to both IRF-1-mediated repression of Cdk2 (15) and the degradation of polyubiquitinated IRF-1 (17). To define components of the IRF-1 interactome whose binding to the Mf1 domain has functional consequences, we set up a biochemical screen for proteins that bind to amino acids 301-320 of IRF-1.…”

Section: Discussionmentioning

confidence: 99%

“…1A) is an important regulatory domain (14 -16). Of particular interest is the Mf1 region (amino acids 301-325) that is essential for maximal IRF-1-mediated growth suppression (15) and that plays a key role in determining the rate of IRF-1 degradation (17). In a quest to identify factors that mediate the regulatory functions of the Mf1 domain, we adapted a biochemical screen (Fig.…”

Section: Identification Of the Molecular Chaperone Hsp70 As A Novel Imentioning

confidence: 99%

“…Most recently studies have shown that Mf1 is also involved in processing of polyubiquitinated IRF-1 by the proteasome (17). Although the Mf1 is involved in multiple regulatory processes (15,17), nothing is currently known about the mechanism of action of this region and how, for example, cellular factors interact with the Mf1 domain to modulate IRF-1-dependent gene expression and growth repressor activity or to promote IRF-1 turnover.In this study, we provide evidence linking IRF-1 to the Hsp70 family and Hsp90, the core components of the molecular chaperone machinery. Originally defined by their role in de novo protein folding and the response to cellular stress (18,19), it is now recognized that the molecular chaperones have diverse functions in processes that include the following: protein folding (19), preventing the aggregation of denatured proteins (20), maintenance of cell signaling and trafficking pathways (21,22), and the assembly and/or disassembly of multiprotein complexes (23,24).…”

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confidence: 99%

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confidence: 99%

“…The enhancer was originally identified as a region required for maximal IRF-1-mediated transactivation, although it does not have intrinsic transactivation potential (13). More recent structurefunction analysis has shown that the enhancer is involved in the recruitment of coactivators to IRF-1 target promoters (14) and that it can facilitate IRF-1-mediated growth suppression (15), as well as being an important determinant of the rate at which IRF-1 is degraded (15)(16)(17). Housed within the enhancer is a multifunctional subdomain that we have named Mf1 (Multifunctional 1; amino acids 301-325).…”

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Cooperative Regulation of the Interferon Regulatory Factor-1 Tumor Suppressor Protein by Core Components of the Molecular Chaperone Machinery

Narayan

Eckert

Żylicz

et al. 2009

Journal of Biological Chemistry

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Our understanding of the post-translational processes involved in regulating the interferon regulatory factor-1 (IRF-1) tumor suppressor protein is limited. The introduction of mutations within the C-terminal Mf1 domain (amino acids 301-325) impacts on IRF-1-mediated gene repression and growth suppression as well as the rate of IRF-1 degradation. However, nothing is known about the proteins that interact with this region to modulate IRF-1 function. A biochemical screen for Mf1-interacting proteins has identified an LXXLL motif that is required for binding of Hsp70 family members and cooperation with Hsp90 to regulate IRF-1 turnover and activity. These conclusions are supported by the finding that Hsp90 inhibitors suppress IRF-1-dependent transcription shortly after treatment, although at later time points inhibition of Hsp90 leads to an Hsp70-dependent depletion of nuclear IRF-1. Conversely, the half-life of IRF-1 is increased by Hsp90 in an ATPase-dependent manner leading to the accumulation of nuclear but not cytoplasmic IRF-1. This study begins to elucidate the role of the Mf1 domain of IRF-1 in orchestrating the recruitment of regulatory factors that can impact on both its turnover and transcriptional activity.Interferon regulatory factor-1 (IRF-1), 3 the founding member of the interferon regulatory factor family, is a transcription factor that regulates a diverse range of target genes during the response to stimuli such as pathogen infection (1), DNA damage (2, 3), and hypoxia (4). In addition, the loss of IRF-1 can cooperate with c-Ha-ras (5) in cellular transformation; it becomes up-regulated in cells that bear oncogenic lesions (6), and deletions of IRF-1 are associated with the development of gastric and esophageal tumors, as well as some leukemias (7-9). On the basis of these observations IRF-1 has been characterized as a tumor suppressor protein. Although initially identified as a component of the IFN␤-enhanceosome complex, IRF-1 has since been demonstrated to regulate the expression of a large cohort of interferon-responsive genes involved in negative growth control (10 -12).Structurally, IRF-1 includes several domains; prominent among these is a highly conserved N-terminal sequence-specific DNA-binding domain, a transactivation domain, and a C-terminal regulatory domain known as the enhancer (13). The enhancer was originally identified as a region required for maximal IRF-1-mediated transactivation, although it does not have intrinsic transactivation potential (13). More recent structurefunction analysis has shown that the enhancer is involved in the recruitment of coactivators to IRF-1 target promoters (14) and that it can facilitate IRF-1-mediated growth suppression (15), as well as being an important determinant of the rate at which IRF-1 is degraded (15-17). Housed within the enhancer is a multifunctional subdomain that we have named Mf1 (Multifunctional 1; amino acids 301-325). This domain impacts on IRF-1-mediated transrepression of the CDK2 gene (14) and is required for maximal IRF-1-mediated...

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Section: Discussionmentioning

confidence: 99%

Section: Identification Of the Molecular Chaperone Hsp70 As A Novel Imentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cooperative Regulation of the Interferon Regulatory Factor-1 Tumor Suppressor Protein by Core Components of the Molecular Chaperone Machinery

Narayan

Eckert

Żylicz

et al. 2009

Journal of Biological Chemistry

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Induction of Samhd1 by interferon gamma and lipopolysaccharide in murine macrophages requires IRF1

et al. 2020

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SAMHD1 is an enzyme with phosphohydrolase activity. Mutations in SAMHD1 have been linked to the development of Aicardi‐Goutières syndrome in humans. This enzyme also has the capacity to restrict HIV virus replication in macrophages. Here, we report that Samhd1 is highly expressed in murine macrophages and is regulated by proinflammatory (IFN‐γ and LPS) but not by anti‐inflammatory (IL‐4 or IL‐10) activators. The induction of Samhd1 follows the pattern of an intermediate gene that requires protein synthesis. In transient transfection experiments using the Samhd1 promoter, we found that a fragment of 27 bps of this gene, falling between −937 and −910 bps relative to the transcription start site, is required for IFN‐γ‐dependent activation. Using EMSAs, we determined that IFN‐γ treatment led to the elimination of a protein complex. Chromatin immunoprecipitation assays and siRNA experiments revealed that IRF1 is required for IFN‐γ‐ or LPS‐induced Samhd1 expression. Therefore, our results indicate that Samhd1 is stimulated by proinflammatory agents IFN‐γ and LPS. Moreover, they reveal that these two agents, via IRF1, eliminate a protein complex that may be related to a repressor, thereby, triggering Samhd1 expression.

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Ubiquitination modification: critical regulation of IRF family stability and activity

Liu

Jin

2020

Sci. China Life Sci.

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Interferon regulatory factors (IRFs) play pivotal and critical roles in innate and adaptive immune responses; thus, precise and stringent regulation of the stability and activation of IRFs in physiological processes is necessary. The stability and activities of IRFs are directly or indirectly targeted by endogenous and exogenous proteins in an ubiquitin-dependent manner. However, few reviews have summarized how host E3 ligases/DUBs or viral proteins regulate IRF stability and activity. Additionally, with recent technological developments, details about the ubiquitination of IRFs have been continuously revealed. As knowledge of how these proteins function and interact with IRFs may facilitate a better understanding of the regulation of IRFs in immune responses or other biological processes, we summarized current studies on the direct ubiquitination of IRFs, with an emphasis on how these proteins interact with IRFs and affect their activities, which may provide exciting targets for drug development by regulating the functions of specific E3 ligases.

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Role of the IRF-1 enhancer domain in signalling polyubiquitination and degradation

Cited by 27 publications

References 34 publications

Cooperative Regulation of the Interferon Regulatory Factor-1 Tumor Suppressor Protein by Core Components of the Molecular Chaperone Machinery

Cooperative Regulation of the Interferon Regulatory Factor-1 Tumor Suppressor Protein by Core Components of the Molecular Chaperone Machinery

Induction of Samhd1 by interferon gamma and lipopolysaccharide in murine macrophages requires IRF1

Ubiquitination modification: critical regulation of IRF family stability and activity

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