Editors' ChoiceCell Biology

Maintaining Membranes

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Science Signaling  15 Nov 2011:
Vol. 4, Issue 199, pp. ec318
DOI: 10.1126/scisignal.4199ec318

Eukaryotic cells are delimited by a membrane that separates the inside from the outside, and they also contain many membrane-defined subcellular compartments. Thus, lipid homeostasis is critically important to cellular function, and dysfunctional lipid homeostasis is associated with various human diseases, including cardiovascular disease and metabolic disorders. Sterol regulatory element–binding proteins (SREBPs) are latent transcriptional regulators located in the endoplasmic reticulum (ER) and are activated in response to cholesterol depletion through relocation to the Golgi, where proteolytic processing occurs. Walker et al. show that SREBP-1 is activated by depletion of phosphatidylcholine (PC), which was achieved experimentally by inhibition of its synthesis. Transcriptional microarray analysis of Caenorhabditis elegans depleted of SBP-1 (the only SREBP ortholog in this worm) revealed that expression of genes implicated in the one-carbon cycle, which is involved in the synthesis of S-adenosylmethionine (SAMe), a methyl donor in PC biosynthesis, was reduced. Worms depleted in a SAMe synthase (encoded by sams-1) exhibited an accumulation of lipid droplets, an accumulation of a green fluorescent protein (GFP)–SBP-1 fusion protein in the nucleus, and an increase in the expression of SBP-1 target genes. An increase in lipid droplet size and nuclear accumulation of SREBP-1 were observed when PC biosynthesis was compromised in human hepatoma cells, and an increase in SREBP-1 processing and target gene expression were observed in the livers of mice with a liver-targeted disruption in PC biogenesis. Knockdown of sams-1 in animals with a hypomorphic sbp-1 allele failed to accumulate the lipid droplets or increase expression of the SBP-1 target genes, and providing dietary choline supplementation rescued these effects of sams-1 knockdown. Although the ER stress response was activated in the sams-1-knockdown animals, RNAi-mediated depletion of downstream signaling molecules in the ER stress response pathway did not prevent lipid droplet accumulation or SBP-1 target gene induction. Furthermore, the nuclear accumulation of SREBP-1 in human hepatoma cells was robust in the absence of the cholesterol-binding chaperone that is required to activate SREBPs in response to cholesterol depletion by promoting the movement of the latent SREBPs from the ER to the Golgi, where the proteolytic processing enzymes reside. Instead, in response to PC depletion, the Golgi appears to become disrupted, resulting in the relocation of the proteolytic enzymes and other Golgi-specific proteins to the ER. Inhibition of the activity of the guanosine triphosphatase ARF with either brefeldin A or knockdown of its exchange factor also caused redistribution of the SREBP-activating proteases and nuclear accumulation of SREBP-1. The authors propose that by altering the ratio of PC to phosphatidylethanolamine in the membranes, depletion of PC may increase membrane curvature, which is known to inhibit ARF activity, and thus promote redistribution of SREBP-processing enzymes and activation of SREBP.

A. K. Walker, R. L. Jacobs, J. L. Watts, V. Rottiers, K. Jiang, D. M. Finnegan, T. Shioda, M. Hansen, F. Yang, L. J. Niebergall, D. E. Vance, M. Tzoneva, A. C. Hart, A. N. Näär, A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans. Cell 147, 840–852 (2011). [Online Journal]

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