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J. Biol. Chem., Vol. 282, Issue 42, 30544-30552, October 19, 2007

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An Endoplasmic Reticulum Transmembrane Prolyl 4-Hydroxylase Is Induced by Hypoxia and Acts on Hypoxia-inducible Factor ^*

Peppi Koivunen^¶, Päivi Tiainen^¶, Jaana Hyvärinen^¶, Kim E. Williams^||, Raija Sormunen^**, Stephen J. Klaus^||, Kari I. Kivirikko^¶, and Johanna Myllyharju^¶1

From the Collagen Research Unit, the Biocenter Oulu, the ^¶Department of Medical Biochemistry and Molecular Biology, and the ^**Department of Pathology, University of Oulu, FIN-90014 Oulu, Finland and ^||FibroGen Inc., South San Francisco, California 94080

Prolyl 4-hydroxylases (P4Hs) act on collagens (C-P4Hs) and the oxygen-dependent degradation domains (ODDDs) of hypoxia-inducible factor subunits (HIF-P4Hs) leading to degradation of the latter. We report data on a human P4H possessing a transmembrane domain (P4H-TM). Its gene is also found in zebrafish but not in flies and nematodes. Its sequence more closely resembles those of the C-P4Hs than the HIF-P4Hs, but it lacks the peptide substrate-binding domain of the C-P4Hs. P4H-TM levels in cultured cells are increased by hypoxia, and P4H-TM is N-glycosylated and is located in endoplasmic reticulum membranes with its catalytic site inside the lumen, a location differing from those of the HIF-P4Hs. Despite this, P4H-TM overexpression in cultured neuroblastoma cells reduced HIF- ODDD reporter construct levels, and its small interfering RNA increased HIF-1 protein level, in the same way as those of HIF-P4Hs. Furthermore, recombinant P4H-TM hydroxylated the two critical prolines in HIF-1 ODDD in vitro, with a preference for the C-terminal proline, whereas it did not hydroxylate any prolines in recombinant type I procollagen chains.

Received for publication, June 18, 2007 , and in revised form, August 14, 2007.

^* This work was supported by Grants 200471 and 202469 from the Health Science Council and Grant 44843 from the Finnish Centre of Excellence Programme 2000–2005 of the Academy of Finland, the S. Jusélius Foundation, and FibroGen Inc. (South San Francisco). 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.

The on-line version of this article (available at http://www.jbc.org) contains experimental details in the supplemental material.

¹ To whom correspondence should be addressed: Collagen Research Unit, Biocenter Oulu and Dept. of Medical Biochemistry and Molecular Biology, P.O. Box 5000, University of Oulu, FIN-90014, Finland. Tel.: 358-8-5375740; Fax: 358-8-5375711; E-mail: johanna.myllyharju{at}oulu.fi.

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