Association of β-arrestin and TRAF6 negatively regulates Toll-like receptor–interleukin 1 receptor signaling

Wang, Yaya; Tang, Yawei; Teng, Lin; Wu, Yalan; Zhao, Xinquan; Pei, Gang

doi:10.1038/ni1294

Cited by 217 publications

(249 citation statements)

References 42 publications

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“…NMDA activation-induced dendrite spine remodeling in neurons is dependent on the scaffolding protein ␤-arrestin-2 (24). This was of interest because ␤-arrestin-2 is known to modulate LPS-induced inflammatory responses, but its role in inflammasome activation is not known (5,22,25,33). Our results clearly show that aspartate-dependent downregulation of inflammasome function in vitro and in vivo is dependent on ␤-arrestin-2.…”

Section: G735supporting

confidence: 52%

Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway

Farooq

Hoque

Ouyang

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Farooq A, Hoque R, Ouyang X, Farooq A, Ghani A, Ahsan K, Guerra M, Mehal WZ. Activation of N-methyl-D-aspartate receptor downregulates inflammasome activity and liver inflammation via a ␤-arrestin-2 pathway. Am J Physiol Gastrointest Liver Physiol 307: G732-G740, 2014. First published August 7, 2014; doi:10.1152/ajpgi.00073.2014.-Activation of the cytosolic inflammasome machinery is responsible for acute and chronic liver inflammation, but little is known about its regulation. The N-methyl-Daspartate (NMDA) receptor families are heterotetrameric ligand-gated ion channels that are activated by a range of metabolites, including aspartate, glutamate, and polyunsaturated fatty acids. In the brain NMDA receptors are present on neuronal and nonneuronal cells and regulate a diverse range of functions. We tested the role of the NMDA receptor and aspartate in inflammasome regulation in vitro and in models of acute hepatitis and pancreatitis. We demonstrate that the NMDA receptor is present on Kupffer cells, and their activation on primary mouse and human cells limits inflammasome activation by downregulating NOD-like receptor family, pyrin domain containing 3 and procaspase-1. The NMDA receptor pathway is active in vivo, limits injury in acute hepatitis, and can be therapeutically further activated by aspartate providing protection in acute inflammatory liver injury. Downregulation of inflammasome activation by NMDA occurs via a ␤-arrestin-2 NF-k␤ and JNK pathway and not via Ca 2ϩ mobilization. We have identified the NMDA receptor as a regulator of inflammasome activity in vitro and in vivo. This has identified a new area of immune regulation associated by metabolites that may be relevant in a diverse range of conditions, including nonalcoholic steatohepatitis and total parenteral nutrition-induced immune suppression.aspartate

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Section: G735supporting

confidence: 52%

Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway

Farooq

Hoque

Ouyang

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In vitro experiments have shown that TRAFs become polyubiquitinated in a Ubc13-dependent manner upon ligation of TNFRs and TLRs (7,22). To determine whether Ubc13 is required for the polyubiquitination of TRAF6 in vivo, we immunoprecipitated TRAF6 from spleen lysates prepared from LPS-treated ubc13 ϩ/Ϫ and ubc13 ϩ/ϩ mice and then analyzed the immunoprecipitated proteins by immunoblotting with antiubiquitin antibody.…”

Section: Ubc13 ؉/؊ Mice Are Born Normally and Exhibit No Abnormalitiementioning

confidence: 99%

Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor-associated factor (TRAF)-mediated inflammatory responses

Fukushima

Matsuzawa

Kress

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

104

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Ubc13 is a ubiquitin-conjugating enzyme responsible for noncanonical ubiquitination of TNF receptor-associated factor (TRAF)-family adapter proteins involved in Toll-like receptor and TNFfamily cytokine receptor signaling, which are regulators of innate immunity. Gene ablation was used to study the function of Ubc13 in mice. Whereas homozygous ubc13 gene disruption resulted in embryonic lethality, heterozygous ubc13 ؉/؊ mice appeared normal, without alterations in immune cell populations. Haploinsufficient ubc13 ؉/؊ mice were resistant to lipopolysaccharide-induced lethality, and demonstrated reduced in vivo ubiquitination of TRAF6. Macrophages and splenocytes isolated from ubc13 ؉/؊ mice exhibited reduced lipopolysaccharide-inducible cytokine secretion and impaired activation of TRAF-dependent signal transduction pathways (NF-B, JNK, and p38 MAPK). These findings document a critical role for Ubc13 in inflammatory responses and suggest that agents reducing Ubc13 activity could have therapeutic utility.inflammation ͉ Toll-like receptor ͉ sepsis ͉ innate immunity

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“…Replicationdeficient adenoviruses encoding GFP-tagged full-length of ␤-arrestin-2 (Arrb2-GFP adenovirus), GFP-tagged ␤-galactosidase (gal-GFP adenovirus), and HA-tagged ␤-arrestin-2 mutant with deletion of its N-terminal (Arrb2-ND-GFP adenovirus) were prepared as before (6,48). The titers of these three adenoviruses were about 1.0 ϫ 10 11 PFU/mL.…”

Section: Microinjection and Expression Of Recombinant Adenovirus In Lamentioning

confidence: 99%

“…␤-arrestin-2 negatively regulates CXCR2-mediated neutrophil chemotaxis (4) and plays a role in allergic-asthmatic inflammation (5). The interaction of ␤-arrestin-2 with TRAF6 negatively modulates Toll-like receptor signaling in innate immunity (6). ␤-arrestin-1 functions as a positive regulator for CD4 ϩ T cell survival and autoimmunity (7).…”

mentioning

confidence: 99%

Regulation of amygdalar PKA by β-arrestin-2/phosphodiesterase-4 complex is critical for fear conditioning

Liu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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␤-arrestins, key regulators of receptor signaling, are highly expressed in the central nervous system, but their roles in brain physiology are largely unknown. Here we show that ␤-arrestin-2 is critically involved in the formation of associative fear memory and amygdalar synaptic plasticity. In response to fear conditioning, ␤-arrestin-2 translocates to amygdalar membrane where it interacts with PDE-4, a cAMP-degrading enzyme, to inhibit PKA activation. Arrb2 ؊/؊ mice exhibit impaired conditioned fear memory and long-term potentiation at the lateral amygdalar synapses. Moreover, expression of the ␤-arrestin-2 in the lateral amygdala of Arrb2 ؊/؊ mice, but not its mutant form that is incapable of binding PDE-4, restores basal PKA activity and rescues conditioned fear memory. Taken together, our data demonstrate that the feedback regulation of amygdalar PKA activation by ␤-arrestin-2 and PDE-4 complex is critical for the formation of conditioned fear memory.

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Association of β-arrestin and TRAF6 negatively regulates Toll-like receptor–interleukin 1 receptor signaling

Cited by 217 publications

References 42 publications

Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway

Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway

Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor-associated factor (TRAF)-mediated inflammatory responses

Regulation of amygdalar PKA by β-arrestin-2/phosphodiesterase-4 complex is critical for fear conditioning

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