Il-17 Signaling Inducibly Degrades Abin1, A Constitutive Inhibitor Of Inflammatory Signaling

Abstract IL-17 is a pro-inflammatory cytokine that drives autoimmune diseases and promotes immunity to fungi. IL-17 binding to the IL-17 receptor initiates recruitment of adaptor proteins that activate NF-κB. IL-17 also induces expression of A20, a feedback inhibitor that restricts NF-κB activation and limits IL-17-dependent inflammation. ABIN1 is an A20 binding protein that has been implicated in autoimmunity in human genetic studies, so we hypothesized that ABIN1 might also play a role in restricting IL-17-dependent signaling. Indeed, ABIN1 inhibited the IL-17 pathway based on RNA silencing analyses. Specifically, the expression of the IL-17-dependent gene lipocalin 2 (Lcn2) increased at both basal levels and after stimulation upon ABIN1 knockdown. Consistently, reconstitution of ABIN1-deficient fibroblasts with ABIN1 also decreased both Lcn2 expression and promoter activation. However, while ABIN1 mRNA increased after IL-17A stimulation, ABIN1 protein progressively decreased following its inducible phosphorylation. Although feedback loops are commonly seen in signaling pathways, differential regulation of mRNA and protein of the same gene are not as common. Thus, we now propose that ABIN1 serves as a constitutive inhibitor of NF-κB signaling. While ABIN1 mRNA is induced by NF-κB at the mRNA level, removal of the ABIN1 protein is required to initiate signal transduction. Unexpectedly, we discovered that A20 is dispensable for both IL-17-mediated degradation of ABIN1 and for ABIN1-dependent inhibition of IL-17 signaling. Altogether, these findings suggest that ABIN1 is a tonic NF-κB inhibitor, and that IL-17 signaling induces its degradation independently of A20 to enhance expression of NF-κB-dependent genes such as Lcn2.