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-6Ralpha), we hypothesized that ARTS-1 might also regulate shedding of IL-6Ralpha, 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-6Ralpha, a size consistent with soluble IL-6Ralpha generated by ectodomain cleavage of the membrane-bound receptor. Furthermore, ARTS-1 promoted IL-6Ralpha shedding, as demonstrated by a direct correlation between increased membrane-associated ARTS-1 protein, increased IL-6Ralpha shedding, and decreased membrane-associated IL-6Ralpha in cell lines overexpressing ARTS-1. The absence of basal IL-6Ralpha shedding from arts-1 knock-out cells identified that ARTS-1 was required for constitutive IL-6Ralpha shedding. Furthermore, the mechanism of constitutive IL-6Ralpha shedding requires ARTS-1 catalytic activity. Thus, ARTS-1 promotes the shedding of two cytokine receptor superfamilies, the type I cytokine receptor superfamily (IL-6Ralpha) and the TNF receptor superfamily (TNFR1). We propose that ARTS-1 is a multifunctional aminopeptidase that may modulate inflammatory events by promoting IL-6Ralpha and TNFR1 shedding.
Highlights
Aminopeptidase regulator of TNFR1 shedding (ARTS-1) binds to the type I tumor necrosis factor receptor (TNFR1) and promotes receptor shedding
In the reciprocal experiment (Fig. 1B), immunoprecipitation with ARTS-1 antiserum pulled down a 55-kDa IL-6R␣ species, which is consistent with the soluble form of IL-6R␣ generated by proteolytic cleavage of the IL-6R␣ extracellular domain
Because both IL-6R␣ and TNFR1 can be co-immunoprecipitated with ARTS-1, we assessed whether the binding of IL-6R␣ and TNFR1 to ARTS-1 is mutually exclusive
Summary
Aminopeptidase regulator of TNFR1 shedding (ARTS-1) binds to the type I tumor necrosis factor receptor (TNFR1) and promotes receptor shedding. In addition to its pro-inflammatory effects, IL-6 has anti-inflammatory functions, such as the suppression of endotoxin-mediated neutrophil recruitment, induction of interleukin-1 receptor antagonist expression, and stimulation of shedding of the 55-kDa, type I tumor necrosis factor receptor (TNFR1, CD120a) as a soluble TNF-binding protein (6 – 8). Binding of the sIL-6R␣1⁄7IL-6 complex to membrane-bound gp130 confers IL-6 signaling capability to cells that do not express IL-6R␣. Trans-signaling via sIL-6R␣1⁄7IL-6 complexes has been identified as an important regulator of CXC and CC chemokine expression that contributes to the termination of neutrophil recruitment and the concurrent influx of mononuclear cells during acute inflammation secondary to bacterial infection [7].
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