Sci. STKE, 19 October 2004
ER STRESS Meeting the Demand
Membrane-associated and secreted proteins are synthesized and undergo early stages of processing--including folding into the proper conformation--within the endoplasmic reticulum (ER). Lipid components of the cell's major membrane system are also synthesized in the ER, but how the amounts of ER proteins and lipids are coordinated is unclear. ER stress, which leads to an increased number of misfolded proteins, elicits the unfolded protein response (UPR). One element of the UPR involves activation of IRE1, an ER transmembrane kinase and endoribonuclease that cleaves the mRNA transcript for the transcription factor X-box binding protein 1 (XBP1) so that it encodes the active [XBP1(S)] rather than the inactive [XBP1(U)] form. XBP1(S) then stimulates the transcription of ER-resident proteins (see Ron and Hampton). Sriburi et al. transduced NIH-3T3 fibroblasts with retroviral vectors encoding XBP1(S) or XBP1(U) and found that cells overexpressing XBP1(S) showed increased ER volume and surface area, as assessed by electron microscopy and immunofluorescence. XBP1(S) cells showed a fourfold increase in phosphatidylcholine synthesis, as judged by incorporation of radiolabeled choline, and increased amounts of both phosphatidylcholine and phosphatidylethanolamine. Further, these cells showed increased activity of enzymes involved in phosphatidylcholine biosynthesis, through what appeared to be a posttranscriptional mechanism. Thus, the authors propose that, in cells undergoing the UPR, XBP1(S) serves to coordinate increased production of ER proteins and lipids to meet the increased cellular demand on the ER.
R. Sriburi, S. Jackowski, K. Mori, J. W. Brewer, XBP1: A link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. J. Cell Biol. 167, 35-41 (2004). [Abstract] [Full Text]
Citation: Meeting the Demand. Sci. STKE 2004, tw371 (2004).
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