Polyubiquitin binding to ABIN1 is required to prevent autoimmunity

Abstract

The polyubiquitin-binding domain of ABIN1 limits TLR-induced MyD88 signaling to prevent spontaneous autoimmunity in mice.

A20-binding inhibitor of NF-κB (ABIN1) controls Toll-like receptor-mediated CCAAT/enhancer-binding protein β activation and protects from inflammatory disease

“…Embryos that were homozygous for this mutant form of ABIN1 did not die during embryogenesis; this result was unexpected given the earlier report demonstrating an essential role of ubiquitin binding in protection from TNF-α-mediated cell death (20). Also unexpected with respect to data obtained from ABIN1-deficient cells described in our work, TLR stimulation of innate immune cells and B cells from ABIN1-mutant mice showed deregulation of both NF-κB-and MAPK-signaling pathways, indicating additional effects of the mutant protein (43). It will be important to compare ABIN1-deficient cells and ABIN1-mutant cells side by side, possibly resolving the apparent discrepancies described.…”

“…the molecular mechanisms involved, with respect to both the proteins involved in ABIN1 recruitment and ABIN1's effector mechanism toward C/EBPβ, need to be established. A very recent report based on a knock-in approach using an ubiquitin-bindingdeficient form of ABIN1 described the development of an autoimmune disease which also involved innate immune cells and lymphocyte activation (43). Embryos that were homozygous for this mutant form of ABIN1 did not die during embryogenesis; this result was unexpected given the earlier report demonstrating an essential role of ubiquitin binding in protection from TNF-α-mediated cell death (20).…”

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

“…Interestingly, the phenomenon of ABIN-1 degradation after an inflammatory stimulus is evident in the published literature, although to our knowledge it has never been remarked upon. For example, ABIN-1 levels decreased after TLR and TNF-a stimulation of bone marrow-derived macrophages with approximately the same kinetics as we observed with IL-17 signaling (35). Additionally, studies in human psoriatic skin lesion biopsies showed increased ABIN-1 mRNA but decreased protein, indicating that this phenomenon occurs in a setting where both IL-17 and ABIN-1 are known to be clinically relevant (11).…”

“…ABIN-1 requires its UBAN for its function, as a D485N mutation within the UBAN suppressed binding to K63 or linear polyubiquitin chains. In vivo, this mutation caused systemic inflammation and autoimmunity (35). This phenotype was considered to be an LPS-mediated response, but involvement of IL-17 was not explored.…”

ABIN1 in the pathogenesis of Glomerulonephritis and the novel polocyte-neutrophil proinflammatory axis.

“…Initial mouse models reported conflicting results when ABIN1 expression was knocked out, resulting in 15 embryonic lethality due to excessive liver apoptosis [51]. This embryonic lethality could be resolved through co-knockdown of the TNF-α receptor 1 alongside ABIN1, Illustration by Erik Korte, unpublished. reported that a knock-in mouse in which wild type ABIN1 was replaced by ABIN1[D485N] induced constitutive activation of NF-κB signaling leading to elevated cytokine production and development of a progressive SLE-like autoimmune disease [53]. Renal injury in these animals was not characterized in this report.…”