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Vol. 17, Issue 9, 3870-3880, September 2006

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Translocation of Endothelial Nitric-Oxide Synthase Involves a Ternary Complex with Caveolin-1 and NOSTRIN

Institute of Biochemistry II, University of Frankfurt Medical School, D-60590 Frankfurt, Germany

Submitted August 2, 2005; Revised June 14, 2006; Accepted June 15, 2006
Monitoring Editor: Robert Parton

Recently, we characterized a novel endothelial nitric-oxide synthase (eNOS)-interacting protein, NOSTRIN (for eNOS-trafficking inducer), which decreases eNOS activity upon overexpression and induces translocation of eNOS away from the plasma membrane. Here, we show that NOSTRIN directly binds to caveolin-1, a well-established inhibitor of eNOS. Because this interaction occurs between the N terminus of caveolin (positions 1–61) and the central domain of NOSTRIN (positions 323–434), it allows for independent binding of each of the two proteins to eNOS. Consistently, we were able to demonstrate the existence of a ternary complex of NOSTRIN, eNOS, and caveolin-1 in Chinese hamster ovary (CHO)-eNOS cells. In human umbilical vein endothelial cells (HUVECs), the ternary complex assembles at the plasma membrane upon confluence or thrombin stimulation. In CHO-eNOS cells, NOSTRIN-mediated translocation of eNOS involves caveolin in a process most likely representing caveolar trafficking. Accordingly, trafficking of NOSTRIN/eNOS/caveolin is affected by altering the state of actin filaments or cholesterol levels in the plasma membrane. During caveolar trafficking, NOSTRIN functions as an adaptor to recruit mediators such as dynamin-2 essential for membrane fission. We propose that a ternary complex between NOSTRIN, caveolin-1, and eNOS mediates translocation of eNOS, with important implications for the activity and availability of eNOS in the cell.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E05-08-0709) on June 28, 2006.

* These authors contributed equally to this work.

Address correspondence to: Werner Müller-Esterl (wme{at}biochem2.de)

Abbreviations used: eNOS, endothelial nitric-oxide synthase; HUVEC, human umbilical vein endothelial cell; Lat A, latrunculin A; MCD, methyl--cyclodextrin; NOSTRIN, endothelial nitric-oxide synthase-trafficking inducer; PM, plasma membrane; TfR, transferring receptor; TGN, trans-Golgi network.

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