Search

TNFAIP3-interacting protein 1 (TNIP1; also known as ABIN-1) is a ubiquitin-binding protein that suppresses death-receptor- or Toll-like receptor-mediated apoptosis and necroptosis; however, it remains unclear whether ABIN-1 is capable of regulating pyroptosis. In the present study, we found that, in mouse embryonic fibroblasts and macrophages, ABIN-1 deficiency sensitized cells to poly(I:C) + TAK1 inhibitor 5Z-7-oxozeaenol-induced pyroptosis besides apoptosis and necroptosis. The sensitizing effect of ABIN-1 deficiency on pyroptosis depended on caspase-8 and its adaptor molecule FAS-associated death domain protein. In a mouse model of polymicrobial sepsis, myeloid-specific deletion of Abin-1 rendered mice more sensitive to pyroptosis, apoptosis and necroptosis, and exacerbated disease severity. Interestingly, ABIN-1 deficiency triggered gasdermin-E-mediated pyroptosis in mouse embryonic fibroblasts, but induced gasdermin-D-mediated pyroptosis in macrophages, both in a caspase-8-dependent manner. Furthermore, we demonstrated that, upon poly(I:C) + 5Z-7-oxozeaenol stimulation, ABIN-1 deficiency facilitates FAS-associated death domain protein recruitment to caspase-8; thus, the mechanism by which ABIN-1 downregulates caspase-8 activity is conserved in tumor necrosis factor receptor type 1 and Toll-like receptor 3 signaling-induced cell death. Together, our work identifies a previously unrecognized role for ABIN-1 as a negative regulator of pyroptosis in addition to apoptosis and necroptosis, suggesting that ABIN-1 represents a promising molecule to halt or reverse progression of refractory inflammatory disorders whose pathogenesis involves multiple forms of programmed cell death., (© 2025 Federation of European Biochemical Societies.)

Deenaz Zaidi,1,2 Hien Q Huynh,1 Matthew W Carroll,1 Shairaz Baksh,1,3,4 Eytan Wine1,2,5 1Department of Pediatrics, 2Department of Medicine, Centre of Excellence for Gastrointestinal Inflammation and Immunity Research (CEGIIR), 3Department of Biochemistry, 4Department of Oncology, Cancer Institute of Northern Alberta (CRINA), 5Department of Physiology, University of Alberta, Edmonton, AB, Canada Purpose: A significant feature of pediatric inflammatory bowel diseases (IBD), which include Crohn disease (CD), and ulcerative colitis (UC), is failure to suppress inflammation. The inability to regulate inflammation renders a major challenge toward establishing effective treatments in IBD. Nuclear factor kappa-light-chain-enhancer of activated B-cells-induced inflammation is inhibited by A20 through interactions with TAX1BP1 (Tax1-binding protein 1) and A20-binding inhibitor of NF-κβ activation (ABIN)-1 (A20 binding and inhibitor of NF-κβ) and upon phosphorylation by inhibitor of nuclear factor kappa-β kinase subunit beta (IKKβ), which stabilizes it. We hypothesized that dysregulation of A20 is an important factor in uncontrolled inflammation in pediatric IBD.Patients and methods: Gene expression of A20, IKKβ, ABIN-1, TAX1BP1, A20 protein, cytokine levels, and A20 phosphorylation was analyzed in the terminal ileum (TI) of 39 patients (14 non-IBD, 15 CD, and 10 UC). A20 expression and protein in T-84 cells and ex vivo biopsies of patients were measured after treatment with Escherichia coli strains or tumor necrosis factor (TNF)-α.Results: TNF-α levels and A20 expression were increased in the TI of CD patients. A20 protein levels and ABIN-1 expression were low, TAX1BP1 expression was high, and IKKβ was unchanged. A20 expression positively correlated with biopsy TNF-α levels and inflammatory markers in CD patients. A20 phosphorylation appeared lower in CD patients. A20 expression in TI biopsies from CD patients and T84 cells was triggered with E. coli, strain LF82, while A20 protein levels remained unchanged.Conclusion: We describe a potential mechanism related to failure of A20 to suppress inflammation in CD, characterized by high A20 expression and low A20 protein levels. The dysregulation of A20 is potentially due to alterations in ABIN-1, and infection with E. coli strain LF82 could affect the function and stability of A20. Our study signifies an important finding in A20 regulation in IBD, which prevents it from suppressing inflammation. Keywords: A20, ABIN-1, inflammation, NF-κβ, TAX1BP1, E. coli

The A20‐binding inhibitor of nuclear factor (NF)‐κB‐1 (ABIN‐1) protein has recently been implicated as a key regulator of inflammation with involvement in multiple inflammatory diseases. However, the function of ABIN‐1 in osteoarthritis (OA) remains unclear. In the current study, we explored the role of ABIN‐1 in the regulation of lipopolysaccharide (LPS)‐induced inflammatory injury of chondrocytes, which served as an in vitro model of OA. Results revealed that ABIN‐1 expression was induced by chondrocyte exposure to LPS. ABN‐1 silencing exacerbated LPS‐induced apoptosis and the inflammatory response, while ABIN‐1 overexpression alleviated the inflammatory response and LPS‐induced apoptosis in chondrocytes. Moreover, ABIN‐1 overexpression resulted in significantly decreased LPS‐induced NF‐κB activation. Notably, activation of NF‐κB signalling significantly reversed ABIN‐1‐mediated inhibitory effects on LPS‐induced inflammatory injury in chondrocytes. Taken together, these results demonstrate that ABIN‐1 protects chondrocytes against LPS‐induced inflammatory injury through the suppression of NF‐κB signalling. Our study suggests a potential role for ABIN‐1 in OA. Further, we show that ABIN‐1 may serve as a potential target for controlling joint inflammation. [ABSTRACT FROM AUTHOR]

The inflammatory repressor TNIP1/ABIN-1 is important for keeping in check inflammatory and cell-death pathways to avoid potentially dangerous sustained activation of these pathways. We have now found that TNIP1 is rapidly degraded by selective macroautophagy/autophagy early (0–4 h) after activation of TLR3 by poly(I:C)-treatment to allow expression of pro-inflammatory genes and proteins. A few hours later (6 h), TNIP1 levels rise again to counteract sustained inflammatory signaling. TBK1-mediated phosphorylation of a TNIP1 LIR motif regulates selective autophagy of TNIP1 by stimulating interaction with Atg8-family proteins. This is a novel level of regulation of TNIP1, whose protein level is crucial for controlling inflammatory signaling. [ABSTRACT FROM AUTHOR]

Although the Ub-binding domain in ABIN proteins and NEMO (UBAN) is highly conserved, UBAN-containing proteins exhibit different Ub-binding properties, resulting in their diverse biological roles. Post-translational modifications further control UBAN domain specificity for poly-Ub chains. However, precisely, how the UBAN domain structurally confers such functional diversity remains poorly understood. Here we report crystal structures of ABIN-1 alone and in complex with one or two M1-linked di-Ub chains. ABIN-1 UBAN forms a homo-dimer that provides two symmetrical Ub-binding sites on either side of the coiled-coil structure. Moreover, crystal structures of ABIN1 UBAN in complex with di-Ub chains reveal a concentration-dependency of UBAN/di-Ub binding stoichiometry. Analysis of UBAN/M1-linked di-Ub binding characteristics indicates that phosphorylated S473 in OPTN and its corresponding phospho-mimetic residue in ABIN-1 (E484) are essential for high affinity interactions with M1-linked Ub chains. Also, a phospho-mimetic mutation of A303 in NEMO, corresponding to S473 of OPTN, increases binding affinity for M1-linked Ub chains. These findings are in line with the diverse physiological roles of UBAN domains, as phosphorylation of OPTN UBAN is required to enhance its binding to Ub during mitophagy. Unlabelled Image • While UBANs are highly conserved domains, they have diverse cellular functions. • ABIN-1 UBAN forms a coiled-coil homo-dimer and binds two M1-linked di-Ubs. • Stoichiometry of UBAN/M1-linked di-Ub binding is concentration-dependent. • Phosphorylation increases affinity of UBANs for M1-linked Ub chains. [ABSTRACT FROM AUTHOR]

TNFAIP3 interacting protein 1 (TNIP1) interacts with numerous non-related cellular, viral, and bacterial proteins. TNIP1 is also linked with multiple chronic inflammatory disorders on the gene and protein levels, through numerous single-nucleotide polymorphisms and reduced protein amounts. Despite the importance of TNIP1 function, there is limited investigation as to how its conformation may impact its apparent multiple roles. Hub proteins like TNIP1 are often intrinsically disordered proteins. Our initial in silico assessments suggested TNIP1 is natively unstructured, featuring numerous potentials intrinsically disordered regions, including the ABIN homology domain 1-ubiquitin binding domain in ABIN proteins and NEMO (AHD1-UBAN) domain associated with its anti-inflammatory function. Using multiple biophysical approaches, we demonstrate the structural flexibility of full-length TNIP1 and the AHD1-UBAN domain. We present evidence the AHD1-UBAN domain exists primarily as a pre-molten globule with limited secondary structure in solution. Data presented here suggest the previously described coiled-coil conformation of the crystallized UBAN-only region may represent just one of possibly multiple states for the AHD1-UBAN domain in solution. These data also characterize the AHD1-UBAN domain in solution as mostly monomeric with potential to undergo oligomerization under specific environmental conditions (e.g., binding partner availability, pH-dependence). This proposed intrinsic disorder across TNIP1 and within the AHD1-UBAN region is likely to impact TNIP1 function and interaction with its multiple partners.

Abstract: A vast number of cellular processes and signaling pathways are regulated by various receptors, ranging from transmembrane to nuclear receptors. These receptor-mediated processes are modulated by a diverse set of regulatory proteins. TNFα-induced protein 3-interacting protein 1 is such a protein that inhibits both transduction by transmembrane receptors, such as TNFα-receptor, EGF-R, and TLR, and nuclear receptors’ PPAR and RAR activity. These receptors play key roles in regulating inflammation and inflammatory diseases. A growing number of references have implicated TNIP1 through GWAS and expression studies in chronic inflammatory diseases such as psoriasis and rheumatoid arthritis, although TNIP1s exact role has yet been determined. In this review, we aim to integrate the current knowledge of TNIP1s functions with the diseases in which it has been associated to potentially elucidate the role this regulator has in promoting or alleviating these inflammatory diseases. [Copyright &y& Elsevier]

Abstract: p105 plays dual roles in NF-κB signaling: in its precursor form it inhibits NF-κB activation, but limited processing by the ubiquitin system generates the p50 active subunit of the transcription factor. Here we show that ABIN-1, an A20-binding protein that is also known to attenuate NF-κB activation, inhibits p105 processing. p105 and ABIN-1 physically interact with one another, but the binding is not necessary for inhibition of processing. Rather, it appears to stabilize ABIN-1 and to increase its level, which further augments its inhibitory effect. Deletion of the processing inhibitory domain (PID) of p105 abrogates the inhibition which also requires the ABIN homology domain (AHD)-2 of ABIN-1. Together, the effects of ABIN-1 on p105 processing and of p105 on stabilizing ABIN-1 act to potentiate the NF-κB inhibitory activity of ABIN-1. [Copyright &y& Elsevier]

TNFAIP3 interacting protein 1 (TNIP1) interacts with numerous non-related cellular, viral, and bacterial proteins. TNIP1 is also linked with multiple chronic inflammatory disorders on the gene and protein levels, through numerous single-nucleotide polymorphisms and reduced protein amounts. Despite the importance of TNIP1 function, there is limited investigation as to how its conformation may impact its apparent multiple roles. Hub proteins like TNIP1 are often intrinsically disordered proteins. Our initial in silico assessments suggested TNIP1 is natively unstructured, featuring numerous potentials intrinsically disordered regions, including the ABIN homology domain 1-ubiquitin binding domain in ABIN proteins and NEMO (AHD1-UBAN) domain associated with its anti-inflammatory function. Using multiple biophysical approaches, we demonstrate the structural flexibility of full-length TNIP1 and the AHD1-UBAN domain. We present evidence the AHD1-UBAN domain exists primarily as a pre-molten globule with limited secondary structure in solution. Data presented here suggest the previously described coiled-coil conformation of the crystallized UBAN-only region may represent just one of possibly multiple states for the AHD1-UBAN domain in solution. These data also characterize the AHD1-UBAN domain in solution as mostly monomeric with potential to undergo oligomerization under specific environmental conditions (e.g., binding partner availability, pH-dependence). This proposed intrinsic disorder across TNIP1 and within the AHD1-UBAN region is likely to impact TNIP1 function and interaction with its multiple partners. [ABSTRACT FROM AUTHOR]