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J. Biol. Chem., Vol. 284, Issue 1, 306-313, January 2, 2009

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Phosphorylation of Serine 271 on 5-Lipoxygenase and Its Role in Nuclear Export^*

Nicolas Flamand, Recipient of a post-doctoral fellowship from the Canadian Institutes of Health Research¹, Ming Luo, Marc Peters-Golden, and Thomas G. Brock

From the Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan 48109 and Centre de recherche de l'Hôpital Laval, Université Laval, Québec City, QC G1V 4G5, Canada

The enzyme 5-lipoxygenase (5-LO) initiates the biosynthesis of leukotrienes, inflammatory mediators involved in immune diseases and defense. The subcellular localization of 5-LO is regulated, with nuclear import commonly leading to increased leukotriene production. We report here that 5-LO is constitutively phosphorylated on Ser-271 in transfected NIH 3T3 cells. This residue is nested in a classical nuclear export sequence, and phosphorylated Ser-271 5-LO was exclusively found in the nucleus by immunofluorescence and by fractionation techniques. Mutation of Ser-271 to Ala allowed nuclear export of 5-LO that was blocked by the specific nuclear export inhibitor leptomycin b, suggesting that phosphorylation of Ser-271 serves to interfere with exportin-1-mediated nuclear export. Consistent with previous reports that purified 5-LO can be phosphorylated on Ser-271 in vitro by MAPK-activated protein kinase 2, the nuclear export of 5-LO was increased by either treatment with the p38 inhibitor SB 203,580 or co-expression of a kinase-deficient p38 MAPK. Nuclear export of 5-LO can also be induced by KN-93, an inhibitor of Ca²⁺/calmodulin-dependent kinase II, and the effects of SB 203,580 plus KN-93 are additive. Finally, HeLa cells, which lack nuclear 5-LO, also lack constitutive phosphorylation of Ser-271. Taken together, these results indicate that the phosphorylation of Ser-271 serves to inhibit the nuclear export of 5-LO. This action works in concert with nuclear import, which is regulated by phosphorylation on Ser-523, to determine the subcellular distribution of 5-LO, which in turn regulates leukotriene biosynthesis.

Received for publication, July 22, 2008 , and in revised form, October 16, 2008.

^* This work was supported by National Institutes of Health Grants RO1 AI43955, HL50496, and HL078727. 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.

¹ To whom correspondence should be addressed: Centre de Recherche de l'Hôpital Laval, Office M2653, 2725 Chemin Sainte-Foy, Québec City, QC G1V 4G5, Canada. Tel.: 418-656-8711 (ext. 3337); E-mail: Nicolas.Flamand{at}crhl.ulaval.ca.

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