BRISC DUB activity as a novel target for lupus
Systemic Lupus Erythematosus (SLE) is strongly associated with dysregulated inflammatory cytokine signaling. Agents that reduce interferon signaling in combination with other inflammatory cytokine production pathways may therefore represent novel and effective strategies against SLE. We have reported that the lysine63-linked ubiquitin (K63-Ub) specific deubiquitinating enzyme (DUB) complex BRISC (BRCC36 isopeptidase complex) deubiqutinates and stabilizes type I interferon receptor in human cells and in vivo in mice (Zheng et al., Cell Reports 2013; Zeqiraj et al. Molecular Cell 2015). BRISC deficient cells and mice exhibit attenuated responses to interferon and dramatic reductions in peritoneal cell invasion, lung hemorrhage, autoantibody formation, and renal pathology following lupus induction from intraperitoneal pristane injection compared to wildtype littermate controls. Commensurate with each of these phenotypes was a strong reduction in interferon responsive gene signatures in BRISC null mice. These studies suggest a therapeutic use of BRISC inhibitors for treating lupus. Importantly, BRISC null mice are viable and fertile, and in contrast to type I interferon inhibition, do not show susceptibility to viruses.
These observations mandate a need to (1) test the hypothesis that BRISC inhibition will mitigate SLE pathogenicity in in vivo models, and (2) the development of specific small molecule inhibitors of BRISC DUB activity. We have recently solved the crystal structure of the minimally active BRISC DUB complex at 2.5 angstroms resolution, giving unprecedented insights into K63-Ub specificity (Zeqiraj et al. Molecular Cell 2015) and rational drug design for BRISC inhibition. Moreover, we have developed a novel high throughput screening approach and identified lead compounds that inhibit BRISC DUB activity with IC50 values in the low micromolar range in vitro and in cells. We will use structure based and rational drug design approaches to optimize lead compounds.
The primary objectives of the proposed research are to (1) determine how BRISC deficiency impacts interferon and other inflammatory cytokine signaling in cells and mice, (2) determine the impact of BRISC inhibition in chemical and genetically induced lupus models, and (3) optimize lead BRISC DUB inhibitors in human cells and in mouse models using rational drug design and screening approaches. The combination of these approaches will provide new insights into the pathophysiology of SLE and may offer novel treatment strategies to mitigate the impact of this disease.