TRAF3 Controls Activation of the Canonical and Alternative NFκB by the Lymphotoxin Beta Receptor

Bista, Pradeep; Zeng, Weike; Ryan, Sarah; Bailly, Véronique; Browning, Jeffrey L.; Lukashev, Matvey

doi:10.1074/jbc.m109.076091

Cited by 74 publications

(81 citation statements)

References 52 publications

(65 reference statements)

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“…Our finding that TRAF3 also inhibits expression of p65 is consistent with the increased p65-binding activity in Traf3 -/-cells (39) and increased phospho-p65 level in TRAF3 knockdown cells in response to TNF or LTβR (40), but the mechanism whereby TRAF3 inhibits NF-κB signaling is unclear. TRAF3 deficiency did not alter protein levels of RANK or DC-STAMP (Supplemental Figure 7, A and B), key regulators of RANKL-induced OCP differentiation and fusion (41,42).…”

Section: Relb Is Required For Rankl-induced Traf3 Lysosomal Degradatisupporting

confidence: 74%

Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation

Xiu¹,

Xu²,

Zhao³

et al. 2013

J. Clin. Invest.

139

180

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The cytokines RANKL and TNF activate NF-κB signaling in osteoclast precursors (OCPs) to induce osteoclast (OC) formation. Conversely, TNF can limit OC formation through NF-κB p100, which acts as an inhibitor, and TNF receptor-associated receptor 3 (TRAF3); however, a role for TRAF3 in RANKL-mediated OC formation is unknown. We found that TRAF3 limits RANKL-induced osteoclastogenesis by suppressing canonical and noncanonical NF-κB signaling. Conditional OC-specific Traf3-KO (cKO) mice had mild osteoporosis and increased OC formation. RANKL induced TRAF3 degradation via the lysosome/autophagy system. The autophagy/lysosome inhibitor chloroquine reduced RANKL-induced OC formation and function by increasing TRAF3 expression in OCPs in vitro and in vivo. Although chloroquine had no effect on basal bone resorption, it inhibited parathyroid hormone-and ovariectomy-induced OC activation in WT, but not cKO, mice. Deletion of the transcription factor gene Relb resulted in increased TRAF3 expression in OCPs, which was associated with decreased RANKL-induced TRAF3 degradation. RelB directly increased expression of BECN1, a key autophagy regulator, by binding to its promoter. These data indicate that autophagic/lysosomal degradation of TRAF3 is an important step in RANKL-induced NF-κB activation in OCPs. Furthermore, treatments that increase TRAF3 levels in OCPs, including pharmacological inhibition of its degradation with compounds such as chloroquine, may limit bone destruction in common bone diseases.

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Section: Relb Is Required For Rankl-induced Traf3 Lysosomal Degradatisupporting

confidence: 74%

Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation

Xiu¹,

Xu²,

Zhao³

et al. 2013

J. Clin. Invest.

139

180

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“…Adaptor molecules that associate with TNF receptors, known as TRAFs, exert a second layer of control over cell-specific TNF-␣ and LIGHT signaling. TRAF3 is basally expressed in neurons but not in glial cells (The Human Protein Atlas [http://www .proteinatlas.org/ENSG00000131323-TRAF3/tissue]), and it has been shown to be much more inducible in neurons than in astrocytes (39). TRAF3 is a negative regulator of LIGHT signaling, as it inhibits the function of the LT␤ receptor, which results in NF-B inactivity (39).…”

Section: Discussionmentioning

confidence: 99%

NF-κB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5′ Long Terminal Repeat

Manghera

Ferguson-Parry

Lin

et al. 2016

J Virol

113

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Thousands of endogenous retroviruses (ERV), viral fossils of ancient germ line infections, reside within the human genome. Evidence of ERV activity has been observed widely in both health and disease. While this is most often cited as a bystander effect of cell culture or disease states, it is unclear which signals control ERV transcription. Bioinformatic analysis suggests that the viral promoter of endogenous retrovirus K (ERVK) is responsive to inflammatory transcription factors. Here we show that one reason for ERVK upregulation in amyotrophic lateral sclerosis (ALS) is the presence of functional interferon-stimulated response elements (ISREs) in the viral promoter. Transcription factor overexpression assays revealed independent and synergistic upregulation of ERVK by interferon regulatory factor 1 (IRF1) and NF-B isoforms. Tumor necrosis factor alpha (TNF-␣) and LIGHT cytokine treatments of human astrocytes and neurons enhanced ERVK transcription and protein levels through IRF1 and NF-B binding to the ISREs. We further show that in ALS brain tissue, neuronal ERVK reactivation is associated with the nuclear translocation of IRF1 and NF-B isoforms p50 and p65. ERVK overexpression can cause motor neuron pathology in murine models. Our results implicate neuroinflammation as a key trigger of ERVK provirus reactivation in ALS. These molecular mechanisms may also extend to the pathobiology of other ERVK-associated inflammatory diseases, such as cancers, HIV infection, rheumatoid arthritis, and schizophrenia. IMPORTANCEIt has been well established that inflammatory signaling pathways in ALS converge at NF-B to promote neuronal damage. Our findings suggest that inflammation-driven IRF1 and NF-B activity promotes ERVK reactivation in neurons of the motor cortex in ALS. Thus, quenching ERVK activity through antiretroviral or immunomodulatory regimens may hinder virus-mediated neuropathology and improve the symptoms of ALS or other ERVK-associated diseases.T housands of endogenous retroviruses (ERV), viral fossils of ancient germ line infections, reside within the human genome. Evidence of ERV activity has been observed widely in both health and disease. While this is most often cited as a bystander effect of cell culture or disease states, it is unclear which signals control ERV transcription and whether their expression is relevant to cellular processes. We previously proposed that the viral promoter of endogenous retrovirus K (ERVK) is responsive to inflammatory transcription factors (1) due to the presence of two conserved interferon-stimulated response elements (ISREs). Thus, select proinflammatory transcription factors may drive ERVK expression.The transcription of integrated retroviral sequences within the human genome is regulated by viral promoters, called long terminal repeats (LTRs), flanking either side of the core viral genome. These LTRs contain transcriptional regulatory elements that are responsive to both viral and cellular transcription factors (TFs). Interferon regulatory factors (IRFs) and nu...

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“…Both the protein kinase Irak2 and adaptor protein Myd88 play key roles in the activation of NFκB [22], whereas Traf3 has been shown to inhibit NFκB activation [23]. The role of the enzyme Ippk is still unclear, but it has been shown to play a role in the inhibition of apoptosis [24].…”

Section: Targets Of β-Adrenergic Transcriptional Responses In Isolatementioning

confidence: 99%

Nuclear β-adrenergic receptors modulate gene expression in adult rat heart

Vaniotis

Duca

Trieu

et al. 2011

Cellular Signalling

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Both β 1 -and β 3 -adrenergic receptors (β 1 ARs and β 3 ARs) are present on nuclear membranes in adult ventricular myocytes. These nuclear-localized receptors are functional with respect to ligand binding and effector activation. In isolated cardiac nuclei, the non-selective βAR agonist isoproterenol stimulated de novo RNA synthesis measured using assays of transcription initiation (Boivin et al., 2006 Cardiovasc Res. 71:69-78). In contrast, stimulation of endothelin receptors, another G protein-coupled receptor (GPCR) that localizes to the nuclear membrane, resulted in decreased RNA synthesis. To investigate the signalling pathway(s) involved in GPCR-mediated regulation of RNA synthesis, nuclei were isolated from intact adult rat hearts and treated with receptor agonists in the presence or absence of inhibitors of different mitogen-activated protein kinase (MAPK) and PI3K/PKB pathways. Components of p38, JNK, and ERK1/2 MAP kinase cascades as well as PKB were detected in nuclear preparations. Inhibition of PKB with triciribine, in the presence of isoproterenol, converted the activation of the βAR from stimulatory to inhibitory with regards to RNA synthesis, while ERK1/2, JNK and p38 inhibition reduced both basal and isoproterenol-stimulated activity. Analysis by qPCR indicated an increase in the expression of 18 S rRNA following isoproterenol treatment and a decrease in NFκB mRNA. Further qPCR experiments revealed that isoproterenol treatment also reduced the expression of several other genes involved in the activation of NFκB, while ERK1/2 and PKB inhibition substantially * Corresponding authors. Hébert is to be contacted

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TRAF3 Controls Activation of the Canonical and Alternative NFκB by the Lymphotoxin Beta Receptor

Cited by 74 publications

References 52 publications

Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation

Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation

NF-κB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5′ Long Terminal Repeat

Nuclear β-adrenergic receptors modulate gene expression in adult rat heart

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