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Molecular and Cellular Biology, May 2007, p. 3758-3768, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.01324-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Peptidyl Prolyl cis/trans Isomerase FKBP38 Determines Hypoxia-Inducible Transcription Factor Prolyl-4-Hydroxylase PHD2 Protein Stability

Sandra Barth,¹ Jutta Nesper,^2, Philippe A. Hasgall,¹ Renato Wirthner,¹ Katarzyna J. Nytko,¹ Frank Edlich,³ Dörthe M. Katschinski,² Daniel P. Stiehl,¹ Roland H. Wenger,¹ and Gieri Camenisch^1*

Institute of Physiology and Center for Integrative Human Physiology, University of Zürich, CH-8057 Zürich, Switzerland,¹ Department of Heart and Circulatory Physiology, Georg August University Göttingen, D-37073 Göttingen, Germany,² Max Planck Research Unit for Enzymology of Protein Folding, D-06120 Halle, Germany³

Received 19 July 2006/ Returned for modification 22 September 2006/ Accepted 25 February 2007

The heterodimeric hypoxia-inducible transcription factors (HIFs) are central regulators of the response to low oxygenation. HIF- subunits are constitutively expressed but rapidly degraded under normoxic conditions. Oxygen-dependent hydroxylation of two conserved prolyl residues by prolyl-4-hydroxylase domain-containing enzymes (PHDs) targets HIF- for proteasomal destruction. We identified the peptidyl prolyl cis/trans isomerase FK506-binding protein 38 (FKBP38) as a novel interactor of PHD2. Yeast two-hybrid, glutathione S-transferase pull-down, coimmunoprecipitation, colocalization, and mammalian two-hybrid studies confirmed specific FKBP38 interaction with PHD2, but not with PHD1 or PHD3. PHD2 and FKBP38 associated with their N-terminal regions, which contain no known interaction motifs. Neither FKBP38 mRNA nor protein levels were regulated under hypoxic conditions or after PHD inhibition, suggesting that FKBP38 is not a HIF/PHD target. Stable RNA interference-mediated depletion of FKBP38 resulted in increased PHD hydroxylation activity and decreased HIF protein levels and transcriptional activity. Reconstitution of FKBP38 expression abolished these effects, which were independent of the peptidyl prolyl cis/trans isomerase activity. Downregulation of FKBP38 did not affect PHD2 mRNA levels but prolonged PHD2 protein stability, suggesting that FKBP38 is involved in PHD2 protein regulation.

Published ahead of print on 12 March 2007.

Present address: Microbiology, University of Konstanz, D-78457 Konstanz, Germany.

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