Emergence of the A20/ABIN-mediated inhibition of NF-κB signaling via modifying the ubiquitinated proteins in a basal chordate

Yuan, Shaochun; Dong, Xiangru; Tao, Xin; Xu, Liqun; Ruan, Jie; Peng, Jian; Xu, Anlong

doi:10.1073/pnas.1321187111

Cited by 20 publications

(18 citation statements)

References 31 publications

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“…In contrast, we did not find a homologous A20 sequence in the genomes of lower invertebrates including Drosophila . Similar to mammalian cells, and as shown here for zebrafish, A20 expression in amphioxus is also regulated by LPS 19,45 and A20 modulates NF-κB signalling utilizing a ubiquitin editing function 13,21,45 . However, the in vivo functional significance of A20 in amphioxus has not been tested 45 .…”

Section: Discussionsupporting

confidence: 63%

“…Similar to mammalian cells, and as shown here for zebrafish, A20 expression in amphioxus is also regulated by LPS 19,45 and A20 modulates NF-κB signalling utilizing a ubiquitin editing function 13,21,45 . However, the in vivo functional significance of A20 in amphioxus has not been tested 45 . Reminiscent of mouse data 1,9 , we found that A20 deficiency in zebrafish was lethal and remarkably re-introduction of human A20 could rescue a proportion of A20-deficient zebrafish from lethality.…”

Section: Discussionsupporting

confidence: 63%

“…A20 inhibits NF-κB activation in mammals in response to TLR signals 1,9 , and uncontrolled NF-κB activation results in excessive inflammation and lethality 44 , yet there is little information regarding the in vivo functional role of A20 beyond studies in mammalian models. An A20-like protein sequence has been identified in the purple sea urchin and amphioxus 45 and in the lamprey genomes 46 and here we identify a functional A20 homologue in zebrafish. In contrast, we did not find a homologous A20 sequence in the genomes of lower invertebrates including Drosophila .…”

Section: Discussionmentioning

confidence: 56%

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A zebrafish functional genomics model to investigate the role of human A20 variantsin vivo

Cultrone

Zammit

Self

et al. 2020

Preprint

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24Germline loss-of-function variation in TNFAIP3, encoding A20, has been implicated in a wide 25 variety of autoinflammatory and autoimmune conditions, with acquired somatic missense 26 mutations linked to cancer progression. Furthermore, human sequence data reveals that the A20 27 locus contains ~400 non-synonymous coding variants which are largely uncharacterised. The 28 growing number of A20 coding variants with unknown function, but potential clinical impact, 29 poses a challenge to traditional mouse-based approaches. Here we report the development of a 30 novel functional genomics approach that utilises the new A20-deficient zebrafish (Danio rerio) 31 model to investigate the impact of TNFAIP3 genetic variants in vivo. Similar to A20-deficient 32 mice, A20-deficient zebrafish are hyper-responsive to inflammatory triggers and exhibit 33 spontaneous early lethality. While ectopic addition of human A20 rescued A20-null zebrafish from 34 lethality, missense mutations at two conserved A20 residues, S381A and C243Y reversed this 35 protective effect. Ser381 represents a phosphorylation site important for enhancing A20 activity 36 that is abrogated by its mutation to alanine, or by a C243Y mutation that associates with human 37 autoimmune disease. These data reveal an evolutionarily conserved role for A20, but also 38 demonstrate how a zebrafish functional genomics pipeline can be utilized to investigate the in vivo 39 significance of medically relevant TNFAIP3 gene variants. This approach could be utilised to 40 investigate genetic variation for other conserved genes. 41 42 45activation 2-6 . The medical importance of A20's role in dampening NF-κB is highlighted by cases 46 of germline A20 loss-of-function mutations in humans who present with severe autoinflammatory 47 disease 7,8 , and by the impact of A20 deletion in mice which results in spontaneous and widespread 48 NF-κB activation, multi-organ inflammation and premature lethality 1,9 . The emergence of A20 49 mutations and coding variants as causal genetic factors driving human disease 10,11 highlight the 50 need to better understand A20's functional domains controlling inflammation in vivo. 51 52 A20 suppresses NF-κB signalling with inhibitory activity against key molecular substrates 53 including signalling molecules TNF receptor-associated factor 6 (TRAF6) 9 , receptor interacting 54 protein 1 (RIP1) 12,13 , and the IκB kinase complex (IKK) 14 . The A20 ovarian-tumour (OTU) 55 domain exhibits deubiquitinating editing (DUB) activity cantered on Cys103, which cleaves 56 activating K63-linked ubiquitin chains from RIPK1, TRAF6 and NEMO to terminate NF-κB 57 signalling 9,12,13,15 . The A20 zinc finger 4 (ZnF4) exhibits E3 ligase activity, adding K48-linked 58 ubiquitin chains to RIPK1, triggering RIPK1 proteolysis 12,16 . In addition, the C-terminal ZnF7 59 domain of A20 binds linear ubiquitin to non-catalytically suppress NF-κB activity 17 . A20 is 60 regulated at the level of gene transcription 6 , whereby NF-κB activation induces TNFAIP3 61 expressi...

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Section: Discussionsupporting

confidence: 63%

Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 56%

See 1 more Smart Citation

A zebrafish functional genomics model to investigate the role of human A20 variantsin vivo

Cultrone

Zammit

Self

et al. 2020

Preprint

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“…Because of its A20-binding capacity, it is frequently assumed that ABIN-1's functions involve A20 (17,31,32). Indeed, ABIN-1 coexpression with A20 was shown to induce destabilization of the IKK complex and inhibition of NF-kB signaling in a lower chordate model organism (33). Similarly, ABIN-1 cooperates with A20 to inhibit antiviral signaling or TNF-regulated NF-kB signaling (20,34).…”

Section: Discussionmentioning

confidence: 99%

IL-17 Signaling Triggers Degradation of the Constitutive NF-κB Inhibitor ABIN-1

et al. 2017

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IL-17 activates NF-κB and inducing expression of proinflammatory genes. IL-17 drives disease in autoimmune conditions, and anti-IL-17 antibodies have shown impressive success in the clinic. Although produced by lymphocytes, IL-17 predominantly signals in fibroblasts and epithelial cells. IL-17-driven inflammation is kept in check by negative feedback signaling molecules, including the ubiquitin editing enzyme A20, whose gene TNFΑIP3 is and similarly linked to autoimmune disease susceptibility. Accordingly, we hypothesized that ABIN-1 might play a role in negatively regulating IL-17 signaling activity. Indeed, ABIN-1 enhanced both tonic and IL-17-dependent NF-κB signaling in IL-17-responsive fibroblast cells. Interestingly, the inhibitory activities of ABIN-1 on IL-17 signaling were independent of A20. ABIN-1 is a known NF-κB target gene, and we found that IL-17-induced activation of NF-κB led to enhanced ABIN-1 mRNA expression and promoter activity. Surprisingly, however, the ABIN-1 protein was inducibly degraded following IL-17 signaling in a proteasome-dependent manner. Thus, ABIN-1, acting independently of A20, restricts both baseline and IL-17-induced inflammatory gene expression. We conclude that IL-17-induced signals lead to degradation of ABIN-1, thereby releasing a constitutive cellular brake on NF-κB activation.

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“…Amphioxus SARM plays inhibitory roles in both MyD88-and TICAM-dependent pathways by interacting with MyD88, TRAF6, and TICAM (19,21). Recently, ubiquitination was shown to be essential in regulating the activation of amphioxus NF-kB (22,23). In addition to these TIR adaptors having homologies with their vertebrate counterparts, most amphioxus TIR adaptors exhibit novel protein domain architectures, such as the TIR domain linked with the kinase domain and the TIR domain linked with the caspase recruitment domain (CARD).…”

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confidence: 99%

Novel Toll/IL-1 Receptor Homologous Region Adaptors Act as Negative Regulators in Amphioxus TLR Signaling

Peng

Tao

et al. 2015

The Journal of Immunology

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Studies have shown that the basal chordate amphioxus possesses an extraordinarily complex TLR system, including 39 TLRs and at least 40 Toll/IL-1R homologous region (TIR) adaptors. Besides homologs to MyD88 and TIR domain-containing adaptor molecule (TICAM), most amphioxus TIR adaptors exhibit domain architectures that are not observed in other species. To reveal how these novel TIR adaptors function in amphioxus Branchiostoma belcheri tsingtauense (bbt), four representatives, bbtTIRA, bbtTIRB, bbtTIRC, and bbtTIRD, were selected for functional analyses. We found bbtTIRA to show a unique inhibitory role in amphioxus TICAM-mediated pathway by interacting with bbtTICAM and bbt receptor interacting protein 1b, whereas bbtTIRC specifically inhibits the amphioxus MyD88-dependent pathway by interacting with bbtMyD88 and depressing the polyubiquitination of bbt TNFR-associated factor 6. Although both bbtTIRB and bbtTIRD are located on endosomes, the TIR domain of bbtTIRB can interact with bbtMyD88 in the cytosol, whereas the TIR domain of bbtTIRD is enclosed in endosome, suggesting that bbtTIRD may be a redundant gene in amphioxus. This study indicated that most expanded TIR adaptors play nonredundant regulatory roles in amphioxus TLR signaling, adding a new layer to understanding the diversity and complexity of innate immunity at basal chordate.

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Emergence of the A20/ABIN-mediated inhibition of NF-κB signaling via modifying the ubiquitinated proteins in a basal chordate

Cited by 20 publications

References 31 publications

A zebrafish functional genomics model to investigate the role of human A20 variantsin vivo

A zebrafish functional genomics model to investigate the role of human A20 variantsin vivo

IL-17 Signaling Triggers Degradation of the Constitutive NF-κB Inhibitor ABIN-1

Novel Toll/IL-1 Receptor Homologous Region Adaptors Act as Negative Regulators in Amphioxus TLR Signaling

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