A model of integrative feedback and homeostasis in lipid biosynthesis

Abstract

Cell membranes exhibit a high degree of species complexity, arising from lipid headgroup and hydrocarbon chain diversity.  It has long been known that these lipid species are under control, but the processes that drive this control remain elusive.  Recently, it was reported that CTP:phosphocholine cytidylyltransferase (CCT), an extrinsic membrane protein that catalyses a rate-limiting step in the synthesis of phosophatidylcholine (PC) lipids, is controlled by the elastic energy stored in the membranes with which it associates (Attard, GS et al (2000) Proc. Natl. Acad. Sci. USA 97, 9032-9036), a property also known as the membrane torque tension (MTT).  Furthermore, the literature on the lipid requirements of the enzymes of phospholipid biosynthesis suggests that control by the MTT may be a general characteristic of these networks.  This leads to the proposal that the property under homeostatic control is the MTT.  This could ensure maintenance of the membrane integrity and provide a mechanism for a non-specific physical integrative feedback signal.

In order to test this hypothesis, a model of the membrane biosynthesis network of eukaryotic cells has been developed to predict the effects of the enzymes of phospholipid biosynthesis on the MTT and to correlate this with the reported lipid dependence.  The predicted locations of these feedback points are in excellent agreement with experimental observations of lipid activation.  The model is also used to investigate the effects of introducing integrative feedback, based on the MTT, at various points in the network.  It is found that feedback at the CCT reaction dramatically increases robustness.  Furthermore, only a few feedback loops are necessary to produce a highly robust network.

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