Peli1 promotes microglia-mediated CNS inflammation by regulating Traf3 degradation

Xiao, Yichuan; Jin, Jin; Chang, Mikyoung; Chang, Jae Hoon; Hu, Hongbo; Zhou, Xiaofei; Brittain, George C.; Stansberg, Carl Trygve; Torkildsen, Øivind; Wang, Xiaodong; Brink, Robert; Cheng, Xuhong; Sun, Shao Cong

doi:10.1038/nm.3111

Cited by 164 publications

(246 citation statements)

References 43 publications

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“…In addition to this newly identified function of TRAF3 in bone homeostasis, TRAF3 has been implicated in the pathogenesis of a number of diseases, including multiple myeloma (63) and experimental autoimmune encephalomyelitis/multiple sclerosis (64). TRAF3 mutations in humans with multiple myeloma result in the accumulation of NIK and constitutive activation of NF-κB, thereby promoting myeloma cell survival.…”

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

confidence: 99%

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 Degradatimentioning

confidence: 99%

Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation

Xiu¹,

Xu²,

Zhao³

et al. 2013

J. Clin. Invest.

139

180

View full text Add to dashboard Cite

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“…Peli1 activates inhibitor of apoptosis‐2, which in turn facilitates the degradation of tumor necrosis factor receptor–associated factor‐3 and liberates MK2 to activate NFκB 33. Accordingly, a deficiency of Peli1 in microglial cells has been shown to be associated with reduced activation of IAP2 and MK2 14. In this study we established that Peli1 could also upregulate MK2 activation in heart tissue to stimulate angiogenesis.…”

Section: Discussionmentioning

confidence: 56%

“…Although the immunological effects of Peli1 have been extensively studied, the involvement of Peli1 in angiogenesis has not yet been examined. Peli1 upregulates MK2 through ubiquitination and activation of inhibitor of apoptosis‐2 (IAP2), which in turn facilitates the ubiquitination and degradation of tumor necrosis factor receptor–associated factor‐3, a negative regulator of MK2 14. Peli1 also plays a role in the activation of NFκB 13.…”

Section: Introductionmentioning

confidence: 99%

Disruption of VEGF Mediated Flk‐1 Signaling Leads to a Gradual Loss of Vessel Health and Cardiac Function During Myocardial Infarction: Potential Therapy With Pellino‐1

Thirunavukkarasu

Selvaraju

Joshi

et al. 2018

JAHA

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BackgroundThe present study demonstrates that the ubiquitin E3 ligase, Pellino‐1 (Peli1), is an important angiogenic molecule under the control of vascular endothelial growth factor (VEGF) receptor 2/Flk‐1. We have previously reported increased survivability of ischemic skin flap tissue by adenovirus carrying Peli1 (Ad‐Peli1) gene therapy in Flk‐1+/− mice.Methods and ResultsTwo separate experimental groups of mice were subjected to myocardial infarction (MI) followed by the immediate intramyocardial injection of adenovirus carrying LacZ (Ad‐LacZ) (1×109 pfu) or Ad‐Peli1 (1×109 pfu). Heart tissues were collected for analyses. Compared with wild‐type (WTMI) mice, analysis revealed decreased expressions of Peli1, phosphorylated (p‐)Flk‐1, p‐Akt, p‐eNOS, p‐MK2, p‐IκBα, and NF‐κB and decreased vessel densities in Flk‐1+/− mice subjected to MI (Flk‐1+/− MI). Mice (CD1) treated with Ad‐Peli1 after the induction of MI showed increased β‐catenin translocation to the nucleus, connexin 43 expression, and phosphorylation of Akt, eNOS, MK2, and IκBα, that was followed by increased vessel densities compared with the Ad‐LacZ–treated group. Echocardiography conducted 30 days after surgery showed decreased function in the Flk1+/− MI group compared with WTMI, which was restored by Ad‐Peli1 gene therapy. In addition, therapy with Ad‐Peli1 stimulated angiogenic and arteriogenic responses in both CD1 and Flk‐1+/− mice following MI. Ad‐Peli1 treatment attenuated cardiac fibrosis in Flk‐1+/− MI mice. Similar positive results were observed in CD1 mice subjected to MI after Ad‐Peli1 therapy.ConclusionOur results show for the first time that Peli1 plays a unique role in salvaging impaired collateral blood vessel formation, diminishes fibrosis, and improves myocardial function, thereby offering clinical potential for therapies in humans to mend a damaged heart following MI.

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“…Another study found that TRAF3 expression was crucial for the Peli1-induced microglia activation in an experimental model of multiple sclerosis (17). Peli1 is an E3 ubiquitin ligase highly expressed in microglia, which regulates microglia activation through the regulation of a signalling pathway which leads to TRAF3 degradation (Table 1) (17).…”

Section: Traf3 and Neurological Diseasesmentioning

confidence: 99%

“…TRAF3 is necessary for sustained B cells activation mediated by LMP1 through the downstream activation of JNK and NF-κβ (Table 1) (14). (13,15,16) NF-κβ, JNK and Rac-1 Stroke, SCI B cell activation (14) NF-κβ and JNK Multiple myeloma, EBV infection Microglia activation (17) MAPK and NF-κβ Multiple sclerosis Osteoclastogenesis (21) NF-κβ Osteoporosis Platelet aggregation (23) Vascular recurrence in patients treated with clopidogrel HIV, human immunodeficiency virus; SCI, spinal cord injury; EBV, Epstein-Barr virus. In addition, CD40, a TNF receptor, and LMP1 share TRAF3 for signal transduction in the activation of B cells (14).…”

Section: Introductionmentioning

confidence: 99%

Role of TRAF3 in neurological and cardiovascular diseases: an overview of recent studies

Cullell

Muiño

Carrera

et al. 2017

Biomolecular Concepts

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Tumour necrosis factor receptor-associated factor 3 (TRAF3) is a member of the TRAF adaptor protein family, which exerts different effects on the cell depending on the receptor to which it binds and the cell type in which it is expressed. TRAF3 is a major regulator of the innate immune response. To perform its functions properly, TRAF3 is transcriptionally and epigenetically regulated. At the transcriptional level, TRAF3 expression has been associated with neurological and cardiovascular diseases including stroke, among other pathologies. Epigenetic modifications of TRAF3 have been observed at the histone and DNA levels. It has been observed that acetylation of TRAF3, as well as other NF-κβ target genes, is associated with cardiac hypertrophy. Furthermore, TRAF3 methylation has been associated with vascular recurrence after ischemic stroke in patients treated with clopidogrel. In this overview, we summarise the most interesting studies related to transcriptional and epigenetic regulation of TRAF3 focusing on those studies performed in neurological and cardiovascular diseases.

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Peli1 promotes microglia-mediated CNS inflammation by regulating Traf3 degradation

Cited by 164 publications

References 43 publications

Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation

Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation

Disruption of VEGF Mediated Flk‐1 Signaling Leads to a Gradual Loss of Vessel Health and Cardiac Function During Myocardial Infarction: Potential Therapy With Pellino‐1

Role of TRAF3 in neurological and cardiovascular diseases: an overview of recent studies

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