The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses

Boone, David L.; Turer, Emre E.; Lee, Eric G.; Ahmad, Regina Celeste; Wheeler, Matthew T.; Tsui, Colleen; Hurley, Paula J.; Chien, Marcia; Chai, Sophia; Hitotsumatsu, Osamu; McNally, Elizabeth M.; Pickart, Cecile M.; Ma, Averil

doi:10.1038/ni1110

Cited by 1,002 publications

(943 citation statements)

References 41 publications

Supporting

Mentioning

906

Contrasting

Unclassified

Order By: Relevance

“…Therefore, other factors need to be investigated to explain the differences. It has been reported that A20, which acts together with Itch, Tax1bp1 and RNF11 in a ubiquitin-editing protein complex [20], inhibits both TNF-and TLR-induced responses [18,19]. For this reason we hypothesised anew that these genes were expressed to a greater extent in C57BL/6 compared to BALB/c mice but again, no significant differences could be detected before or after LPS treatment.…”

Section: Discussionmentioning

confidence: 87%

“…Therefore, the contractile responses to carbachol, 5-HT and bradykinin were studied on tracheal segments, fresh or following in vitro exposure to TNFα, polyinosinic:polycytidylic acid (poly I:C) or lipopolysacharide (LPS) for 4 days (activating TNF receptor, TLR3 and TLR4 pathways respectively) while maintained under normal tissue-culture conditions. To evaluate whether altered expression of signalling proteins contributed to differences in the inflammatory response of tracheal segments from C57BL/6 and BALB/c mice, mRNA levels of TLR, the pivotal inflammatory signal transduction proteins JNK, p38 and p65, together with the critical negative regulators of inflammation A20, Itch, Tax1bp1 and RNF11 [18,19], were quantified in tracheal smooth muscle strips.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inflammation-induced airway smooth muscle responsiveness is strain dependent in mice

Säfholm¹,

Lövdahl²,

Swedin³

et al. 2011

Pulmonary Pharmacology & Therapeutics

View full text Add to dashboard Cite

Different mouse strains display different degrees of inflammation-induced airway hyperresponsiveness in vivo. It is not known whether these variations are attributable to distinct properties of the airway smooth muscle. Therefore, tracheal ring segments from C57BL/6 and BALB/c mice were exposed to three different pro-inflammatory stimuli for 4 days while maintained under tissue-culture conditions: tumour necrosis factor α (100 ng/ml), the Toll-like receptor (TLR) 3 agonist polyI:C (10 µg/ml), and the TLR4 agonist LPS (10 µg/ml). The contractile responses to carbachol, 5-hydroxytryptamine (5-HT) and bradykinin were assessed after culture. In addition, gene expression of TLR1-TLR9, pivotal inflammatory signal transduction proteins (jun-kinase, p38 and p65) and critical negative regulators of inflammation (A20, Itch, Tax1bp1 and RNF11) were studied in tracheal smooth muscle strips, fresh and following treatment for 4 days with LPS, from both strains. No differences between the strains were detected regarding the response of freshly isolated preparations to carbachol, 5-HT and bradykinin. After stimulation with pro-inflammatory mediators, contractions in response to 5-HT and bradykinin, but not to carbachol, were up-regulated. This up-regulation was markedly larger in BALB/c than in C57BL/6 segments and depended on the type of inflammatory stimulus. Expression of the genes investigated did not differ between the two strains. These findings indicate that strain differences in airway hyperresponsiveness can be linked to differences in the responsiveness of airway smooth muscle to pro-inflammatory mediators per se. These differences do not appear to be due to differential expression of TLR or common inflammatory transduction and repressor proteins.

show abstract

Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Inflammation-induced airway smooth muscle responsiveness is strain dependent in mice

Säfholm¹,

Lövdahl²,

Swedin³

et al. 2011

Pulmonary Pharmacology & Therapeutics

View full text Add to dashboard Cite

show abstract

“…This suggests that A20 HET does not result in hyperactivation of the innate or adaptive immune system as homozygous KO does. 13,33 However, intrahepatic levels of TNF and IL-6 following PH were excessively higher and prolonged in HET versus WT livers 4d post PH, likely contributing to derailed LR. 17 This indicates that maladaptive inflammatory responses in HET mice only unveil following injury (in this case PH), and remain contained to the site of injury (here the liver) as systemic inflammation did not worsen.…”

Section: Discussionmentioning

confidence: 99%

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

et al. 2015

View full text Add to dashboard Cite

Hepatic expression of A20, including in hepatocytes, increases in response to injury, inflammation and resection. This increase likely serves a hepatoprotective purpose. The characteristic unfettered liver inflammation and necrosis in A20 knockout mice established physiologic upregulation of A20 as integral to the anti-inflammatory and anti-apoptotic armamentarium of hepatocytes. However, the implication of physiologic upregulation of A20 in modulating hepatocytes' proliferative responses following liver resection remains controversial. To resolve the impact of A20 on hepatocyte proliferation and the liver's regenerative capacity, we examined whether decreased A20 expression, as in A20 heterozygous knockout mice, affects outcome following two-third partial hepatectomy. A20 heterozygous mice do not demonstrate a striking liver phenotype, indicating that their A20 expression levels are still sufficient to contain inflammation and cell death at baseline. However, usually benign partial hepatectomy provoked a staggering lethality (440%) in these mice, uncovering an unsuspected phenotype. Heightened lethality in A20 heterozygous mice following partial hepatectomy resulted from impaired hepatocyte proliferation due to heightened levels of cyclin-dependent kinase inhibitor, p21, and deficient upregulation of cyclins D1, E and A, in the context of worsened liver steatosis. A20 heterozygous knockout minimally affected baseline liver transcriptome, mostly circadian rhythm genes. Nevertheless, this caused differential expression of 41000 genes post hepatectomy, hindering lipid metabolism, bile acid biosynthesis, insulin signaling and cell cycle, all critical cellular processes for liver regeneration. These results demonstrate that mere reduction of A20 levels causes worse outcome post hepatectomy than full knockout of bona fide liver pro-regenerative players such as IL-6, clearly ascertaining A20's primordial role in enabling liver regeneration. Clinical implications of these data are of utmost importance as they caution safety of extensive hepatectomy for donation or tumor in carriers of A20/TNFAIP3 single nucleotide polymorphisms alleles that decrease A20 expression or function, and prompt the development of A20-based liver proregenerative therapies. Humans and mice restore their liver mass within 2 weeks of surgical, viral or toxic parenchymal loss via compensatory regrowth, referred to as liver regeneration (LR). 1,2 Adequate LR is contingent upon maintaining a minimum healthy residual liver mass without which hepatocyte proliferation is stunned, resulting in hepatic failure. In liver transplantation (mainly living donor liver transplantation), 'small-for-size' syndrome illustrates this outcome. 3 Incremental 78% and 87% hepatectomy in mice reproduces this syndrome, causing 50% and 100% lethality, respectively. 4 Despite considerable knowledge characterizing the molecular basis of LR, better understanding of this process's shortcomings in the face of extensive resection and/or damage is required for uncovering therapie...

show abstract

“…The N-terminal deubiquitinating domain of A20 mediates the removal of K63-polyubiquitin chains from RIP1, whereas the C-terminal zinc finger domain catalyzes RIP1 K48-polyubiquitination, thereby targeting RIP1 for proteasomal degradation [7]. Similarly, A20 has been shown to inhibit lipopolysaccharide (LPS)-induced NF-B activation by de-ubiquitinating K63-polyubiquitinated TRAF6 [8], but A20-mediated K48-ubiquitination of TRAF6 has not yet been reported.…”

Section: Introductionmentioning

confidence: 99%

ABINs: A20 binding inhibitors of NF-κB and apoptosis signaling

Verstrepen¹,

Carpentier²,

Verhelst³

et al. 2009

Biochemical Pharmacology

157

126

View full text Add to dashboard Cite

ABINs have been described as three different proteins (ABIN-1, ABIN-2, that bind the ubiquitin-editing nuclear factor-B (NF-B) inhibitor protein A20 and which show limited sequence homology. Overexpression of ABINs inhibits NF-B activation by tumor necrosis factor (TNF) and several other stimuli. Similar to A20, ABIN-1 and ABIN-3 expression is NF-B dependent, implicating a potential role for the A20/ABIN complex in the

show abstract

The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses

Cited by 1,002 publications

References 41 publications

Inflammation-induced airway smooth muscle responsiveness is strain dependent in mice

Inflammation-induced airway smooth muscle responsiveness is strain dependent in mice

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

ABINs: A20 binding inhibitors of NF-κB and apoptosis signaling

Contact Info

Product

Resources

About