A20 and ABIN-1 synergistically preserve intestinal epithelial cell survival

Abstract

A20 () and ABIN-1 () are candidate susceptibility genes for inflammatory bowel disease and other autoimmune or inflammatory diseases, but it is unclear how these proteins interact in vivo to prevent disease. Here we show that intestinal epithelial cell (IEC)-specific deletion of either A20 or ABIN-1 alone leads to negligible IEC loss, whereas simultaneous deletion of both A20 and ABIN-1 leads to rapid IEC death and mouse lethality. Deletion of both A20 and ABIN-1 from enteroids causes spontaneous cell death in the absence of microbes or hematopoietic cells. Studies with enteroids reveal that A20 and ABIN-1 synergistically restrict death by inhibiting TNF-induced caspase 8 activation and RIPK1 kinase activity. Inhibition of RIPK1 kinase activity alone, or caspase inhibition combined with RIPK3 deletion, abrogates IEC death by blocking both apoptosis and necroptosis in A20 and ABIN-1 double-deficient cells. These data show that the disease susceptibility proteins A20 and ABIN-1 synergistically prevent intestinal inflammation by restricting IEC death and preserving tissue integrity.

Transcriptome Profiling of Bovine Macrophages Infected by Mycobacterium avium spp. paratuberculosis Depicts Foam Cell and Innate Immune Tolerance Phenotypes

“…Our results suggest that MAP may prevent apoptosis by upregulating TNIP1 and its protein-protein partner TNFAIP3 (A20). This mechanism is known to synergistically impair procaspase 8 recruitment (110). The reduction of caspase 8 activity was observed in primary bovine macrophages infected by MAP (108).…”

Enhanced Wound Healing- and Inflammasome-Associated Gene Expression in TNFAIP3-Interacting Protein 1- (TNIP1-) Deficient HaCaT Keratinocytes Parallels Reduced Reepithelialization

“…It is particularly interesting then that these TNIP1-deficient, low DAMP/PAMP conditions yielded decreased phosphorylated A20, a posttranslational modification that increases A20 functionality and recruitment to suppress inflammatory signaling [51,66]. Thus, as supported by recent findings [11,67], it will be important to consider individual and pairwise anti-inflammatory roles of TNIP1 and A20 and the possible differences in cell death due to their deficiency or dysfunction [68].…”

“…A20 transcription is positively regulated by NF-κB [50,51]. At the protein level, A20 facilitates some of the inflammatory signal-suppressing properties of TNIP1 though both can act independently in this regard [11]. Given this, we examined A20 expression being especially interested in its levels in TNIP1-deficient, poly (I:C) exposed cells where induction of several NF-κBregulated genes were upregulated and cell viability was reduced.…”

“…TNIP1 limits cytoplasmic signal progression downstream of TLR, TNF-R, and EGF-R, thus protecting cells from inopportune NF-κB-, IRF3-, and ERK-mediated transcription (see [4,8] for review). Expression studies in multiple cell and tissue types have demonstrated that experimentally derived TNIP1 deficiency or knockout initiates and/or enhances inflammatory phenotypes [9][10][11][12][13], often recapitulating pathologies known for their relapsing or chronic immune activation. Given that human pathologies such as psoriasis, lupus, and scleroderma [12,14,15] are associated with reduced TNIP1 protein levels, as opposed to being expression null, we modeled cells deficient in TNIP1 protein and their responses to limiting amounts of likely encountered cell membrane receptor signaling molecules to assess for possible synergistic effects of the two conditions.…”

Multitasking Kinase RIPK1 Regulates Cell Death and Inflammation

“…The cIAPs contribute to the assembly of TNFR1 complex I as described above, but may also limit activation of RIPK1 by modifying RIPK1 with Lys48-linked polyubiquitin that targets it for proteasomal degradation (Varfolo-meev et al 2008;Dynek et al 2010;Annibaldi et al 2018). Genetic studies in mice implicate XIAP and A20 in the suppression of RIPK1 activation (Wong et al 2014;Onizawa et al 2015;Newton et al 2016a;Kattah et al 2018;Rijal et al 2018), but the underlying biochemical mechanism in each case is still being elucidated. The binding of A20 to Met1-linked polyubiquitin in TNFR1 complex I appears to be critical to limiting TNF-induced cell death (Draber et al 2015;Yamaguchi and Yamaguchi 2015;Polykratis et al 2019).…”