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J. Biol. Chem., Vol. 278, Issue 31, 28677-28685, August 1, 2003

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An Aminopeptidase, ARTS-1, Is Required for Interleukin-6 Receptor Shedding^*

Xinle Cui, Farshid N. Rouhani , Feras Hawari  and Stewart J. Levine 

From the Pulmonary-Critical Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-1590

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-6R), we hypothesized that ARTS-1 might also regulate shedding of IL-6R, 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-6R, a size consistent with soluble IL-6R generated by ectodomain cleavage of the membrane-bound receptor. Furthermore, ARTS-1 promoted IL-6R shedding, as demonstrated by a direct correlation between increased membrane-associated ARTS-1 protein, increased IL-6R shedding, and decreased membrane-associated IL-6R in cell lines overexpressing ARTS-1. The absence of basal IL-6R shedding from arts-1 knock-out cells identified that ARTS-1 was required for constitutive IL-6R shedding. Furthermore, the mechanism of constitutive IL-6R shedding requires ARTS-1 catalytic activity. Thus, ARTS-1 promotes the shedding of two cytokine receptor superfamilies, the type I cytokine receptor superfamily (IL-6R) and the TNF receptor superfamily (TNFR1). We propose that ARTS-1 is a multifunctional aminopeptidase that may modulate inflammatory events by promoting IL-6R and TNFR1 shedding.

Received for publication, January 15, 2003 , and in revised form, May 10, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Pulmonary-Critical Care Medicine Branch, Bldg. 10, Rm. 6D03, MSC 1590, NHLBI, National Institutes of Health, Bethesda, MD 20892-1590. E-mail: levines{at}nhlbi.nih.gov.

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