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J. Biol. Chem., Vol. 282, Issue 24, 17537-17547, June 15, 2007

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Both Sphingomyelin Synthases SMS1 and SMS2 Are Required for Sphingomyelin Homeostasis and Growth in Human HeLa Cells^*

Fikadu Geta Tafesse¹, Klazien Huitema¹, Martin Hermansson, Seléne van der Poel, Joep van den Dikkenberg, Andreas Uphoff, Pentti Somerharju, and Joost C. M. Holthuis²

From the Department of Membrane Enzymology, Bijvoet Center and Institute of Biomembranes, Utrecht University, 3584 CH Utrecht, The Netherlands and Department of Biochemistry, Institute of Biomedicine, University of Helsinki, Helsinki 00014, Finland

Sphingomyelin (SM) is a vital component of cellular membranes in organisms ranging from mammals to protozoa. Its production involves the transfer of phosphocholine from phosphatidylcholine to ceramide, yielding diacylglycerol in the process. The mammalian genome encodes two known SM synthase (SMS) isoforms, SMS1 and SMS2. However, the relative contributions of these enzymes to SM production in mammalian cells remained to be established. Here we show that SMS1 and SMS2 are co-expressed in a variety of cell types and function as the key Golgi- and plasma membrane-associated SM synthases in human cervical carcinoma HeLa cells, respectively. RNA interference-mediated depletion of either SMS1 or SMS2 caused a substantial decrease in SM production levels, an accumulation of ceramides, and a block in cell growth. Although SMS-depleted cells displayed a reduced SM content, external addition of SM did not restore growth. These results indicate that the biological role of SM synthases goes beyond formation of SM.

Received for publication, March 21, 2007

^* This work was supported by grants from the Dutch Organization of Sciences (NWO-CW) and the Utrecht University High Potential Program (to J. C. M. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Membrane Enzymology, Bijvoet Center and Inst. of Biomembranes, Utrecht University, H. R. Kruytgebouw, Padualaan 8, 3584 CH Utrecht, The Netherlands. Tel.: 31-30-253-6630; Fax: 31-30-252-2478; E-mail: j.c.holthuis{at}chem.uu.nl.

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