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Vol. 16, Issue 3, 1120-1130, March 2005

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The Rate-limiting Enzyme in Phosphatidylcholine Synthesis Regulates Proliferation of the Nucleoplasmic Reticulum

Atlantic Research Center, Departments of Pediatrics and Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7

Submitted October 7, 2004; Revised December 2, 2004; Accepted December 16, 2004
Monitoring Editor: Jean Gruenberg

The nucleus contains a network of tubular invaginations of the nuclear envelope (NE), termed the nucleoplasmic reticulum (NR), implicated in transport, gene expression, and calcium homeostasis. Here, we show that proliferation of the NR, measured by the frequency of NE invaginations and tubules, is regulated by CTP:phosphocholine cytidylyltransferase- (CCT), the nuclear and rate-limiting enzyme in the CDP–choline pathway for phosphatidylcholine (PtdCho) synthesis. In Chinese hamster ovary (CHO)-K1 cells, fatty acids triggered activation and translocation of CCT onto intranuclear tubules characteristic of the NR. This was accompanied by a twofold increase in NR tubules quantified by immunostaining for lamin A/C or the NE. CHO MT58 cells expressing a temperature-sensitive CCT allele displayed reduced PtdCho synthesis and CCT expression and minimal proliferation of the NR in response to oleate compared with CHO MT58 cells stably expressing CCT. Expression of CCT mutants in CHO58 cells revealed that both enzyme activity and membrane binding promoted NR proliferation. In support of a direct role for membrane binding in NR tubule formation, recombinant CCT caused the deformation of liposomes into tubules in vitro. This demonstrates that a key nuclear enzyme in PtdCho synthesis coordinates lipid synthesis and membrane deformation to promote formation of a dynamic nuclear-cytoplasmic interface.

Abbreviations used: CK, choline kinase, Con A, concanavalin A; CPT, choline phosphotransferase; CCT, CTP:phosphocholine cytidylyltransferase; DAG, diacylglycerol; EM, electron microscopy; LPDS; lipoprotein deficient serum; NE, nuclear envelope; NR, nucleoplasmic reticulum; NPC, nuclear pore complex; PtdCho, phosphatidylcholine; PDI, protein disulfide isomerase.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

^* Present address: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390.

Address correspondence to: Neale D. Ridgway (nridgway{at}dal.ca).

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