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J. Biol. Chem., Vol. 279, Issue 17, 17338-17347, April 23, 2004

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Development of Protein-based Inhibitors of the Proprotein of Convertase SKI-1/S1P

PROCESSING OF SREBP-2, ATF6, AND A VIRAL GLYCOPROTEIN^*

Philomena Pullikotil, Martin Vincent, Stuart T. Nichol, and Nabil G. Seidah¶

From the Laboratories of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada and the Special Pathogens Branch, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333

Processing of membrane-bound transcription factors such as sterol regulatory element-binding proteins (SREBPs) and the ER-stress response factor ATF6, and glycoproteins of some hemorrhagic fever viruses are initiated by the proprotein convertase SKI-1/S1P. So far, no cellular protein-based inhibitor of the hydrophobic-amino acid specific SKI-1 is known. The prosegment of the basic-amino acid specific convertases (e.g. furin and PC5) or ₁-PDX, a variant of ₁-antitrypsin (₁-AT) exhibiting an RIPR³⁵⁸ sequence at the reactive site loop, were shown to potently inhibit these secretory proteinases. Accordingly, we tested the SKI-1-inhibitory potential of various point mutants of either the 198 amino acid preprosegment of SKI-1-(1–198) or ₁-AT. Transient transfections data showed that, out of numerous mutants studied, the R134E prosegment mutant or the ₁-AT reactive site loop variants RRVL³⁵⁸, RRYL³⁵⁸ and RRIL³⁵⁸ are the best specific cellular inhibitors of SKI-1. The observed inhibition of the processing of endogenous SREBP-2, exogenous ATF6 and a PDGF-A (RRLL⁸⁶) variant were >55% and reach 80% in stable transfectants. We also show that SKI-1 forms SDS-stable complexes with these ₁-AT variants, but not with wild-type ₁-AT or ₁-PDX. Finally, these inhibitors were also shown to affect the processing and stability of the Crimean-Congo hemorrhagic fever virus glycoprotein.

Received for publication, December 16, 2003 , and in revised form, January 20, 2004.

^* This work was supported by a Canadian Institutes of Health Research (CIHR) Grant MOP-36496, and by the Protein Engineering Network of Excellence (PENCE). 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.

^¶ To whom correspondence should be addressed: Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, 110 Pine Ave. West Montreal, QC H2W 1R7 Canada. Tel.: 514-987-5609; Fax: 514-987-5542; E-mail: seidahn{at}ircm.qc.ca.

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