The nuclear membrane organization of leukotriene synthesis

doi:10.1073/pnas.0808211106

The nuclear membrane organization of leukotriene synthesis

^aRenal Unit, Massachusetts General Hospital, Building 149-The Navy Yard, 13th Street, Charlestown, MA 02129;
^bDepartment of Neurology and Alzheimer's Disease Research Laboratory, Massachusetts General Hospital, Building 114-The Navy Yard, 16th Street, Charlestown MA, 02129;
^cMerck Research Laboratories, Rahway, NJ 07065; and
^dDivision of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115

Edited by K. Frank Austen, Brigham and Women's Hospital, Boston, MA, and approved November 4, 2008 (received for review August 19, 2008)

Abstract

Leukotrienes (LTs) are signaling molecules derived from arachidonic acid that initiate and amplify innate and adaptive immunity. In turn, how their synthesis is organized on the nuclear envelope of myeloid cells in response to extracellular signals is not understood. We define the supramolecular architecture of LT synthesis by identifying the activation-dependent assembly of novel multiprotein complexes on the outer and inner nuclear membranes of mast cells. These complexes are centered on the integral membrane protein 5-Lipoxygenase-Activating Protein, which we identify as a scaffold protein for 5-Lipoxygenase, the initial enzyme of LT synthesis. We also identify these complexes in mouse neutrophils isolated from inflamed joints. Our studies reveal the macromolecular organization of LT synthesis.

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Footnotes

¹To whom correspondence should be addressed. E-mail: Soberman{at}helix.mgh.harvard.edu
Author contributions: A.K.M., P.B.J., P.C., J.F.E., B.T.H., B.B., M.C., D.M.L., and R.J.S. designed research; A.K.M., P.B.J., M.C., and D.M.L. performed research; D.M., T.-t.D.Y., D.W., and J.M. contributed new reagents/analytic tools; A.K.M., P.B.J., A.M.B., P.C., D.M., T.-t.D.Y., D.W., J.M., J.F.E., B.T.H., B.B., M.C., D.M.L., B.N., and R.J.S. analyzed data; and A.K.M., P.B.J., A.M.B., J.F.E., and R.J.S. wrote the paper.
Conflict of interest statement: All financial and material support for this research and work are clearly identified in the manuscript. In particular, Dr. Peter Christmas was supported by a grant from Merck Research Labs, Rahway, NJ, and Dr. Roy Soberman received unrestricted charitable gifts from Merck Research Labs and from Merck Frosst, Canada.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0808211106/DCSupplemental.