IndraLab
Statements
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"In this context, TNIP1, also known as ABIN (A20-binding inhibitor of NF-κB)-1, is a polyubiquitin-binding protein that interacts with TNFAIP3 to facilitate the binding of TNFAIP3 to polyubiquitinated mediators of NF-κB activation, and thus promotes the inhibition of NF-κB by TNFAIP3."
eidos
"Since numerous inflammatory stimuli via cognate receptors converge to activate NF-kappaB , we examined whether SKBHT suppresses the activity of NF-kappaB by inducing TNFAIP3 , an ubiquitin-modulating protein that suppresses proinflammatory signaling originating from receptors for IL-1beta , TNF-alpha , or LPS [ 31 ] ."
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"It was proved that TNFAIP3, a key factor in NF-kappaB pathway, could attenuate NF-kappaB activation during the infection [XREF_BIBR] while nAChR, one of important ACh receptor, could also modulate the inflammatory responses through both NF-kappaB and JAK and STAT pathway [XREF_BIBR, XREF_BIBR]."
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"A20 inhibits several key upstream signal transduction pathways of NF-kB induced by Toll-like receptor (TLR), the tumor necrosis factor receptor (TNFR), and retinoic acid-inducible gene I (RIG-I) in a feedback manner xref – xref by ubiquitination or deubiquitination of receptor interacting protein (RIP), TNFR-associated factor (TRAF) 6, and other molecules for either promoting target protein degradation or regulating interaction of the target proteins with other signaling molecules xref – xref ."
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"XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Other genes negatively regulate NF-kappaB activation, such as the TNF alpha induced protein 3 (TNFAIP3; A20), a ubiquitin editing enzyme which downregulates NF-kappaB signaling when binding TNFAIP3 interacting proteins 1 and 2 (TNIP1 and TNIP2, respectively)."
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"Therefore, this model may be more relevant in T and B lymphocytes where the basal levels of A20 are high. xref Taken together, it has become increasingly clear that A20 may inhibit NF-κB independently of its deubiquitinase activity, although additional studies are clearly needed to further test and refine the different models of A20 inhibition of NF-κB."
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"T cell co-stimulation with a 4-1BB agonist antibody triggers K63 ubiquitination of 4-1BB-associated TRAF2, which is crucial for NF-κB activation and induction of antitumor immunity. xref Conversely, the 4-1BB signaling is negatively regulated by two DUBs, CYLD and A20, which physically associate with the 4-1BB/TRAF2 complex. xref Overexpression of either CYLD or A20 inhibits NF-κB activation by the 4-1BB agonist antibody, whereas silencing these DUBs enhances NF-κB activation mediated by 4-1BB costimulation in human CD8 T cells. xref The role of K63 ubiquitination in 4-1BB-mediated CD8 T cell costimulation is further supported by the finding that CD8 effector and memory T cells expressing a dominant-negative mutant of the E3 ligase cIAP2 (cIAP2 H570A ) have attenuated 4-1BB signaling and impaired survival, demonstrated using a viral infection model. xref "
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"In addition to its well-ascribed functions as a DUB and ubiquitin-editing enzyme, there is also evidence that A20 may inhibit NF-κB via non-catalytic mechanisms. xref , xref For example, A20 disrupts the binding between E2 and E3 ubiquitin enzyme complexes to terminate IL-1R/TLR4 signaling. xref As mentioned earlier, a recent study suggests that A20 may also directly inhibit IKK through a noncatalytic mechanism dependent on ubiquitin binding via zinc finger domains. xref Therefore, what are the precise roles of the A20 OTU domain and the C-terminal zinc fingers in NF-κB and cell death inhibition?"
eidos
"Indeed , TNFAIP3 interferes with TLR ( Toll-like receptors ) and NOD2 ( nucleotide-binding oligomerization domain 2 ) signaling pathways to limit NF-kappaB activation and pro-inflammatory cytokine production [ 41,42 ] , which may help infected IECs to limit the pro-inflammatory responses induced by AIEC infection [ 8,9 ] ."
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"Among the cell lines studied, LY3 carries an activating mutation in CARD11 [XREF_BIBR] (XREF_SUPPLEMENTARY); LY3, LY10, U2932 (ABC) along with LY8, VAL, and SUDHL2 (GCB) carry inactivating mutations or hemizygous deletion in TNFAIP3 (A20), which negatively regulates NFkappaB activity."
eidos
"A20 not only inhibits NF-kappaB signalling by modifying ubiquitylated protein substrates in multiple ways , but also blocks type I IFN signalling by removing K63-linked ubiquitin chains from TBK1 / IKKi , which is activated by the RIG-I / MDA5-mitochondrial antiviral signaling protein axis [ 21 ] ."
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"This was based upon the published studies that A20, a zinc-finger ubiquitin-modifying enzyme, inhibits several upstream signaling pathways of NF-kB in a feedback manner by degradation or deactivation of signaling molecules via its dual functions of ubiquitination and deubiquitination xref , xref , xref ; A20-deficient Mфs display prolonged NF-κB activity xref , xref ; A20-silenced dendritic cells (DCs) express higher levels of costimulatory molecules and proinflammatory cytokines, and display a superior immunostimulatory ability xref ."
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"Despite the important insight into A20 function from initial studies with A20-deficient mice, it was still yet to be elucidated how A20 inhibited NF-κB. A20 was subsequently found to contain an OTU DUB domain embedded in its N-terminus. xref , xref Overexpression of A20, but not a catalytically inactive DUB mutant, inhibited both RIP1 and TRAF6 ubiquitination. xref , xref A20 also contains seven C-terminal zinc finger domains, one of which functions as an E3 ligase."