Nuclear Import of Arachidonate 5-Lipoxygenase

  • Thomas G. Brock
  • Annette M. Healy


Leukotrienes are lipid messenger molecules that are secreted by leukocytes to orchestrate a rapid and prolonged immune response. The enzyme 5-lipoxygenase catalyzes the rate-limiting first two steps in the synthesis of leukotrienes from arachidonic acid. Although it has long been known that 5-lipoxygenase moves from the cytoplasm to a membrane following activation, it has only recently been recognized that the enzyme may shuttle into and out of the nucleus before activation. The regulation of this movement of soluble 5-lipoxygenase between the cytoplasm and the nucleoplasm, as well as its impact on 5-lipoxygenase action, leukotriene synthesis and cell function, is only now being elucidated. This review details the state of our understanding of the nuclear import of 5-lipoxygenase and its potential importance in immunity.

Key words

lukotrienes 5-lipoxygenase nuclear import. 



arachidonic acid


5-lipoxygenase activating protein


5-hydroperoxyeicosatetraenoic acid


5-hydroxyeicostatetraenoic acid






nuclear importsequence


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abramovitz M., Wong E., Cox M., Richardson C., Li C. and Vickers P. (1993): 5-Lipoxygenase-activating protein stimulates the utilization of arachidonic acid by 5-lipoxygenase. Eur. J. Biochem., 215, 105–111.Google Scholar
  2. Bailie M., Standiford T., Laichalk L., Coffey M., Strieter R. and Peters-Golden M. (1996): Leukotriene-deficient mice manifest enhanced lethality from Klebsiella pneumonia in association with decreased alveolar macrophage phagocytic and bactericidal activities. J. Immunol., 157, 5221–5224.PubMedGoogle Scholar
  3. Baiter M., Toews G. and Peters-Golden M. (1989): Different patterns of arachidonate metabolism in autologous human blood monocytes and alveolar macrophages. J. Immunol., 142, 602–608.Google Scholar
  4. Brock T., Anderson J., Fries F., Peters-Golden M. and Sporn P. (1999): Decreased leukotriene C4 synthesis accompanies nuclear import of 5-lipoxygenase in human blood eosinophils. J. Immunol., 162, 1669–1676.PubMedGoogle Scholar
  5. Brock T., McNish R., Bailie M. and Peters-Golden M. (1997): Rapid import of cytosolic 5-lipoxygenase into the nucleus of neutrophils after in vivo recruitment and in vitro adherence. J. Biol. Chem., 272, 8276–8280.PubMedCrossRefGoogle Scholar
  6. Brock T., McNish R. and Peters-Golden M. (1998): Capacity for repeatable leukotriene generation following transient stimulation of mast cells and macrophages. Biochem. J. 329, 519–525.PubMedGoogle Scholar
  7. Brock T. G., Paine R. and Peters-Golden M. (1994): Localization of 5-lipoxygenase to the nucleus of unstimulated rat basophilic leukemia cells. J. Biol. Chem., 269, 22059–22066.PubMedGoogle Scholar
  8. Chakraborti T., Mandat M., Das S. and Chakraborti S. (1999): Age-dependent change in arachi- donic acid metabolic capacity in rat alveolar macrophages. Biochem. Mol. Biol. Int., 47, 501–507.PubMedGoogle Scholar
  9. Chen X.-S., Zhang Y-Y. and Funk C. (1998): Determinants of 5-lipoxygenase nuclear localization using green fluorescent protein-5-lipoxygenase fusion proteins. J. Biol. Chem., 273, 31237–31244.PubMedCrossRefGoogle Scholar
  10. Coffey M., Phare S., Kazanjian P. and Peters-Golden M. (1996): 5-Lipoxygenase metabolism in alveolar macrophages from subjects infected with the human immunodeficiency virus. J. Immunol., 157, 393–399.Google Scholar
  11. Covin R., Brock T., Bailie M. and Peters-Golden M. (1998): Altered expression and localization of 5-lipoxygenase accompany macrophage differentiation in the lung. Am. J. Physiol., 275, L303 — L310.PubMedGoogle Scholar
  12. Cowburn A., Holgate S. and Sampson A. (1999): IL-5 increases expression of 5-lipoxygenasepactivating protein and translocates 5-lipoxygenase to the nucleus in human blood eosinophils. J. Immunol., 163, 456–465.PubMedGoogle Scholar
  13. Devchand P., Keller H., Peters J., Vazquez M., Gonzalez F. and Wahli W. (1996): The PPARaGleukotriene B4 pathway to inflammation control. Nature, 384, 39–43.PubMedCrossRefGoogle Scholar
  14. Dixon R. A. F., Diehl R. E., Opas E., Rands E., Vickers P. J., Evans J. F., Gillard J. W. and Miller D. K. (1990): Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Nature, 343, 282–284.Google Scholar
  15. Drazen J. M., Lilly C. M., Sperling R., Rubin P. and Israel E. (1994): Role of cysteinyl leukotrienes in spontaneous asthmatic responses. Adv. Prostaglandin Thromboxane Leukot. Res., 22, 251–262.Google Scholar
  16. Gorlich D. (1997): Nuclear protein import. Curr. Opin. Cell Biol., 9, 412–419.PubMedCrossRefGoogle Scholar
  17. Gorlich D. and Kutay U. (1999): Transport between the cell nucleus and the cytoplasm. Annu. Rev. Cell Dev. Biol., 15, 607–660.PubMedCrossRefGoogle Scholar
  18. Healy A., Peters-Golden M., Yao J. and Brock T. (1999): Identification of a bipartite nuclear localization sequence necessary for nuclear import of 5-lipoxygenase. J. Biol. Chem., 274, 29812–29818.PubMedCrossRefGoogle Scholar
  19. Hill E., Maclouf J., Murphy R. and Henson P. (1992): Reversible membrane association of neutrophil 5-lipoxygenase is accompanied by retention of activity and a change in substrate specificity. J. Biol. Chem., 267, 22048–22053.PubMedGoogle Scholar
  20. Lepley R. A. and Fitzpatrick F. (1994a): 5-lipoxygenase contains a functional Src homology 3-binding motif that interacts with the Src homology 3 domain of Grb2 and cytoskeletal proteins. J. Biol. Chem., 269, 24163–24168.Google Scholar
  21. Lepley R. A. and Fitzpatrick F. (1994b): Irreversible inactivation of 5-lipoxygenase by leukotriene A4. Characterization of product inactivation with purified enzyme and intact leukocytes. J. Biol. Chem., 269, 2627–2631.PubMedGoogle Scholar
  22. Lepley R. and Fitzpatrick F. (1996): Inhibition of mitogen-activated protein kinase kinase blocks activation and redistribution of 5-lipoxygenase in HL-60 cells. Arch. Biochem. Biophys., 331, 141–144.PubMedCrossRefGoogle Scholar
  23. Lepley R., Muskardin D. and Fitzpatrick F. (1996): Tyrosine kinase activity modulates catalysis and translocation of cellular 5-lipoxygenase. J. Biol. Chem., 271, 6179–6184.PubMedCrossRefGoogle Scholar
  24. Lynch K. R., O’Neil G. P., Liu Q., Im D. S., Sawyer N., Metters K. M., Coulombe N., Abramovitz M., Figueroa D. J., Zeng Z., Connolly B. M., Bai C., Austin C. P., Chateauneuf A., Stocco R., Grieig G. M., Kargman S., Hooks S. B., Hosfield E., Williams D. L. Jr., Ford--Hutchinson A. W., Caskey C. T. and Evans J. F. (1999): Characterization of the human cysteinyl leukotriene CysLT, receptor. Nature, 399, 789–793.PubMedCrossRefGoogle Scholar
  25. Malaviya R., Malaviya R. and Jakschik B. A. (1993): Reversible translocation of 5-lipoxygenase in mast cells upon IgE/antigen stimulation. J. Biol. Chem., 268, 4939–4944.PubMedGoogle Scholar
  26. McMillan R., Master D., Vickers V., Dicken M. and Jacobs V. (1989): Metabolism of unsaturated fatty acids by RBL-1 5-lipoxygenase: influence of substrate solubility and product inactivation. Biochim. Biophys. Acta, 1005, 170–176.Google Scholar
  27. Nakielny S. and Dreyfuss G. (1999): Transport of proteins and RNAs in and out of the nucleus. Cell Press, 99, 677–690.CrossRefGoogle Scholar
  28. Needleman P., Turk J., Jakschik B. A., Morrison A. R. and Lefkowith J. B. (1986): Arachidonic acid metabolism. Annu. Rev. Biochem., 55, 69–102.PubMedCrossRefGoogle Scholar
  29. Penrose J., Spector J., Lam B., Friend D., Xu K., Jack R. and Austen K. (1995): Purification of human lung LTC4 synthase and preparation of a polyclonal antibody. Am. J. Respir. Crit. Care Med., 152, 283–289.PubMedGoogle Scholar
  30. Peters-Golden M., McNish R. W., Hyzy R., Shelly C. and Toews G. B. (1990): Alterations in the pattern of arachidonate metabolism accompany rat macrophage differentiation in the lung. J. Immunol., 144, 263–270.PubMedGoogle Scholar
  31. Provost P., Samuelsson B. and Radmark O. (1999): Interaction of 5-lipoxygenase with cellular proteins. Proc. Natl. Acad. Sci., USA, 96, 1881–1885.Google Scholar
  32. Rachelefsky G. (1997): Childhood asthma and allergic rhinitis: the role of leukotrienes. J. Pediatr., 131, 348–355.PubMedCrossRefGoogle Scholar
  33. Rouzer C. A. and Kargman S. (1988): Translocation of 5-lipoxygenase to the membrane in human leukocytes challenged with ionophore A23187. J. Biol. Chem., 263, 10980–10988.PubMedGoogle Scholar
  34. Samuelsson B. and Funk C. D. (1989): Enzymes involved in the biosynthesis of leukotriene B4. J. Biol. Chem., 264, 19469–19472.PubMedGoogle Scholar
  35. Viggiano D., Romano G., Caniglia M., Santoro P., Palumbo A. and Cicimarra F. (1994): Impaired leukotriene B4 release by neonatal polymorphonuclear leukocytes. Pediatr. Res., 36, 60–63.PubMedCrossRefGoogle Scholar
  36. Wilborn J., Bailie M., Coffey M., Burdick M., Strieter R. and Peters-Golden M. (1996): Constitutive activation of 5-lipoxygenase in the lungs of patients with idiopathic pulmonary fibrosis. J. Clin. Invest., 97, 1827–1836.PubMedCrossRefGoogle Scholar
  37. Woods J., Coffey M., Brock T., Singer I. and Peters-Golden M. (1995): 5-Lipoxygenase is located in the euchromatin of the nucleus in resting human alveolar macrophages and translocates to the nuclear envelope upon cell activation. J. Clin. Invest., 95, 2035–2040.Google Scholar
  38. Yokomizo T., Izumi T., Chang K., Takuwa Y. and Shimizu T. (1997): A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature, 387, 620–624.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2001

Authors and Affiliations

  • Thomas G. Brock
    • 1
  • Annette M. Healy
    • 1
  1. 1.Department of Internal MedicineUniversity of MichiganAnn ArborUSA

Personalised recommendations