An aminopeptidase, ARTS-1, is required for interleukin-6 receptor shedding

Abstract

Aminopeptidase regulator of TNFR1 shedding (ARTS-1) binds to the type I tumor necrosis factor receptor (TNFR1) and promotes receptor shedding. Because hydroxamic acid-based metalloprotease inhibitors prevent shedding of both TNFR1 and the interleukin-6 receptor (IL-6Rα), we hypothesized that ARTS-1 might also regulate shedding of IL-6Rα, a member of the type I cytokine receptor superfamily that is structurally different from TNFR1. Reciprocal co-immunoprecipitation experiments identified that membrane-associated ARTS-1 directly binds to a 55-kDa IL-6Rα, a size consistent with soluble IL-6Rα generated by ectodomain cleavage of the membrane-bound receptor. Furthermore, ARTS-1 promoted IL-6Rα shedding, as demonstrated by a direct correlation between increased membrane-associated ARTS-1 protein, increased IL-6Rα shedding, and decreased membrane-associated IL-6Rα in cell lines overexpressing ARTS-1. The absence of basal IL-6Rα shedding from arts-1 knock-out cells identified that ARTS-1 was required for constitutive IL-6Rα shedding. Furthermore, the mechanism of constitutive IL-6Rα shedding requires ARTS-1 catalytic activity. Thus, ARTS-1 promotes the shedding of two cytokine receptor superfamilies, the type I cytokine receptor superfamily (IL-6Rα) and the TNF receptor superfamily (TNFR1). We propose that ARTS-1 is a multifunctional aminopeptidase that may modulate inflammatory events by promoting IL-6Rα and TNFR1 shedding.