The Anti-inflammatory Prostaglandin 15-Deoxy-Δ12,14-PGJ2 Inhibits CRM1-dependent Nuclear Protein Export*

  1. Ralph H. Kehlenbach§,3
  1. From the ‡UCD Conway Institute, Belfield, Dublin 4, Ireland and
  2. the §Department of Biochemistry I, Faculty of Medicine, Georg-August-University of Göttingen, Humboldtallee 23, 37073 Göttingen, Germany
  1. 3 To whom correspondence should be addressed. Tel.: 49-551-395950; Fax: 49-551-395960; E-mail: rkehlen{at}gwdg.de.

  • ↵2 Present address: Mass Spectrometry Resource Conway Institute, UCD, Belfield, Ireland.

  1. ↵1 Both authors contributed equally to this work.

Abstract

The signaling molecule 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) has been described as the “anti-inflammatory prostaglandin.” Here we show that substrates of the nuclear export receptor CRM1 accumulate in the nucleus in the presence of 15d-PGJ2, identifying this prostaglandin as a regulator of CRM1-dependent nuclear protein export that can be produced endogenously. Like leptomycin B (LMB), an established fungal CRM1-inhibitor, 15d-PGJ2 reacts with a conserved cysteine residue in the CRM1 sequence. This covalent modification prevents the formation of nuclear export complexes. Cells that are transfected with mutant CRM1 (C528S) are resistant to the inhibitory effects of LMB and 15d-PGJ2, demonstrating that the same single amino acid is targeted by the two compounds. Inhibition of the CRM1 pathway by endogenously produced prostaglandin and/or exogenously applied 15d-PGJ2 may contribute to its anti-inflammatory, anti-proliferative, and anti-viral effects.

Footnotes

  • ↵* This work was funded in part by a Research Program Grant, Faculty of Medicine, Georg-August-University, Göttingen (to R. H. K.) and by the Health Research Board of Ireland and the Cancer Research Ireland (to D. J. F.).

  • ↵Graphic The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

  • Received April 9, 2010.
  • Revision received May 6, 2010.
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  1. First Published on May 10, 2010 doi: 10.1074/jbc.M110.131821 The Journal of Biological Chemistry 285, 22202-22210.
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