Query author contributions in Reactome
Reactome depends on collaboration between our curation team and outside experts to assemble and peer-review its pathway modules. The integration of ORCID within Reactome enables us to meet a key challenge with authoring, curating and reviewing biological information by incentivizing and crediting the external experts that contribute their expertise and time to the Reactome curation process. More information is available at ORCID and Reactome.
If you have an ORCID ID that is not listed on this page, please forward this information to us and we will update your Reactome pathway records.
Details on Person Expression of TNFAIP3 (also known as A20) is upregulated by ...
| Class:Id | Summation:5693056 |
|---|---|
| _displayName | Expression of TNFAIP3 (also known as A20) is upregulated by ... |
| _timestamp | 2022-08-31 20:24:59 |
| created | [InstanceEdit:5693058] Shamovsky, Veronica, 2015-05-13 |
| literatureReference | [LiteratureReference:939841] De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling [LiteratureReference:5692387] Inhibition of NF-kappaB signaling by A20 through disruption of ubiquitin enzyme complexes [LiteratureReference:5693057] Essential role for TAX1BP1 in the termination of TNF-alpha-, IL-1- and LPS-mediated NF-kappaB and JNK signaling [LiteratureReference:5692376] A20 inhibits tumor necrosis factor (TNF) alpha-induced apoptosis by disrupting recruitment of TRADD and RIP to the TNF receptor 1 complex in Jurkat T cells [LiteratureReference:6793319] Dimerization and ubiquitin mediated recruitment of A20, a complex deubiquitinating enzyme [LiteratureReference:6793304] Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-κB regulation [LiteratureReference:6793309] The deubiquitinase activity of A20 is dispensable for NF-κB signaling [LiteratureReference:6793314] A20 inhibits LUBAC-mediated NF-κB activation by binding linear polyubiquitin chains via its zinc finger 7 [LiteratureReference:6793311] Direct, noncatalytic mechanism of IKK inhibition by A20 |
| modified | [InstanceEdit:5693173] Shamovsky, Veronica, 2015-05-14 [InstanceEdit:6793330] Shamovsky, Veronica, 2015-09-01 [InstanceEdit:9816042] Shamovsky, Veronica, 2022-08-31 |
| text | Expression of TNFAIP3 (also known as A20) is upregulated by NFkappaB activation. TNFAIP3 (A20) is believed to inhibit NFkappaB with the help of its ubiquitin-editing functions (Wertz IE et al, 2004). The N-terminal half of TNFAIP3 harbors a deubiquitinating (DUB) domain that mediates the deubiquitination of K63-polyubiquitinated substrates such as receptor interacting protein 1 (RIPK1), an essential mediator of the proximal TNFR1 signalling complex (Shembade N et al. 2010; Wertz IE et al. 2004). The carboxy-terminal domain of TNFAIP3 (A20), composed of seven C2/C2 zinc fingers, functions as a ubiquitin ligase by polyubiquitinating target proteins with K48-linked ubiquitin chains, thereby targeting them for proteasomal degradation (Wertz IE et al. 2004). TNFAIP3 zinc fingers have been also shown to support TNFAIP3's binding to different ubiquitinated molecules (Wertz IE et al. 2004; Shembade N et al. 2010; Lu TT et al. 2013). The Reactome pathway shows that upon TNF receptor 1 (TNFR1) stimulation, the E3 ubiquitin ligases such as baculoviral IAP repeat-containing protein (BIRC2/3 or cIAP1/2) mediate polyubiquitination of RIPK1 generating K63-linked chains. TNFAIP3 removes these K63-linked polyubiquitin chains, preventing the interaction of RIPK1 with NFkappaB essential modulator (NEMO) (Wertz IE et al. 2004). Subsequently, TNFAIP3 facilitates addition of K48-linked polyubiquitin chains to RIPK1, targeting it for proteasomal degradation (Wertz IE et al. 2004). In this way, TNFAIP3 restricts TNF-induced NFkappaB signaling by sequential deubiquitination and ubiquitin-mediated degradation of RIPK1. TNFAIP3 (A20) is thought to limit NFkappaB activation, however the inhibitory mechanisms for TNFAIP3 are not fully understood and are partially contradicting. A study with knockin mice expressing DUB-inactive Tnfaip3 C103A mutant reported that the deubiquitinase (DUB) activity was dispensable for LPS- or TNF-stimulated NFkappaB signaling (De A et al 2014). In contrast to Tnfaip3 knockout mice that develop perinatal lethality, the knockin Tnfaip3 C103A mice were normal and did not have an inflammatory phenotype (De A et al 2014). These finding are in agreement with an earlier study reporting that the Tnfaip3 C103A knockin mice were grossly normal for at least 4 months and contained a normal number of lymphocytes (Lu TT et al. 2013). In addition, bone marrow-derived macrophage cells (BMDM) from the knockin mice showed normal LPS- and TNF-induced NFkappaB activation and downstream gene expression, comparable to cells from wild-type mice (De A et al 2014). The study suggests that the deubiquitinase activity of TNFAIP3 in general is not obligate for most of the regulatory functions of TNFAIP3 and alternative mechanisms might be involved in TNFAIP3-mediated NFkappaB regulation (De A et al 2014). Indeed, there is biochemical evidence for different mechanisms that may contribute to TNFAIP3 inhibitory effects on TNFR1 pro-inflammatory signaling in a cell type-dependent manner:
TAX1BP1 functions as an adaptor molecule for TNFAIP3 (A20) to block TNF-alpha-stimulated signaling to NFkappaB (Shembade N et al. 2007). |
| (summation) | [Reaction:5693055] TAX1BP1:TNFAIP3(A20) binds RIPK1-containing complexes [Homo sapiens] |
| [Change default viewing format] | |
