Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter October 23, 2013

Crosstalk of lipid and protein homeostasis to maintain membrane function

Claudius Stordeur, Kristina Puth, James P. Sáenz and Robert Ernst
From the journal Biological Chemistry

Abstract

Biological membranes are a defining feature of cellular life. They serve as selective diffusion barriers, compartmentalize biochemical processes and protect the cellular milieu. We are only beginning to understand the principles underlying their homeostasis and the functional relevance of their complex compositions. Here, we summarize some recent evidences that suggest an intense crosstalk between the pathways of protein quality control and lipid homeostasis. We discuss paradigms of lipid regulation by protein degradation machineries and highlight the intricate connections between lipid droplet morphology, membrane biogenesis and ER-stress.


Corresponding author: Robert Ernst, Institute of Biochemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany, e-mail:

We apologize to all of our colleagues, whose work could not be cited. R.E. acknowledges Kai Simons and his lab, especially Robin W. Klemm, for important discussions as well as the Deutsche Forschungsgemeinschaft for support (Emmy Noether Program ER608/2-1 and SFB807 Transport and Communication across Biological Membranes).

References

Alberts, S.M., Sonntag, C., Schafer, A., and Wolf, D.H. (2009). Ubx4 modulates Cdc48 activity and influences degradation of misfolded proteins of the endoplasmic reticulum. J. Biol. Chem. 284, 16082–16089.10.1074/jbc.M809282200Search in Google Scholar PubMed PubMed Central

Alexandru, G., Graumann, J., Smith, G.T., Kolawa, N.J., Fang, R., and Deshaies, R.J. (2008). UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1alpha turnover. Cell 134, 804–816.10.1016/j.cell.2008.06.048Search in Google Scholar PubMed PubMed Central

Auld, K.L. and Silver, P.A. (2006). Transcriptional regulation by the proteasome as a mechanism for cellular protein homeostasis. Cell Cycle 5, 1503–1505.10.4161/cc.5.14.2979Search in Google Scholar PubMed

Bernales, S., McDonald, K.L., and Walter, P. (2006a). Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. 4, e423.10.1371/journal.pbio.0040423Search in Google Scholar PubMed PubMed Central

Bernales, S., Papa, F.R., and Walter, P. (2006b). Intracellular signaling by the unfolded protein response. Annu. Rev. Cell Dev. Biol. 22, 487–508.10.1146/annurev.cellbio.21.122303.120200Search in Google Scholar PubMed

Bernales, S., Schuck, S., and Walter, P. (2007). ER-phagy: selective autophagy of the endoplasmic reticulum. Autophagy 3, 285–287.10.4161/auto.3930Search in Google Scholar PubMed

Bhattacharya, S., Shcherbik, N., Vasilescu, J., Smith, J.C., Figeys, D., and Haines, D.S. (2009). Identification of lysines within membrane-anchored Mga2p120 that are targets of Rsp5p ubiquitination and mediate mobilization of tethered Mga2p90. J. Mol. Biol. 385, 718–725.10.1016/j.jmb.2008.11.018Search in Google Scholar PubMed PubMed Central

Bigay, J. and Antonny, B. (2012). Curvature, lipid packing, and electrostatics of membrane organelles: defining cellular territories in determining specificity. Dev. Cell 23, 886–895.10.1016/j.devcel.2012.10.009Search in Google Scholar PubMed

Braun, S., Matuschewski, K., Rape, M., Thoms, S., and Jentsch, S. (2002). Role of the ubiquitin-selective CDC48(UFD1/NPL4) chaperone (segregase) in ERAD of OLE1 and other substrates. EMBO J. 21, 615–621.10.1093/emboj/21.4.615Search in Google Scholar PubMed PubMed Central

Bretscher, M.S. and Munro, S. (1993). Cholesterol and the Golgi apparatus. Science 261, 1280–1281.10.1126/science.8362242Search in Google Scholar PubMed

Brown, M.S. and Goldstein, J.L. (2009). Cholesterol feedback: from Schoenheimer’s bottle to Scap’s MELADL. J. Lipid Res. 50, S15–S27.10.1194/jlr.R800054-JLR200Search in Google Scholar

Buchberger, A., Howard, M.J., Proctor, M., and Bycroft, M. (2001). The UBX domain: a widespread ubiquitin-like module. J. Mol. Biol. 307, 17–24.10.1006/jmbi.2000.4462Search in Google Scholar

Carvalho, P., Goder, V., and Rapoport, T.A. (2006). Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 126, 361–373.10.1016/j.cell.2006.05.043Search in Google Scholar

Chellappa, R., Kandasamy, P., Oh, C.S., Jiang, Y., Vemula, M., and Martin, C.E. (2001). The membrane proteins, Spt23p and Mga2p, play distinct roles in the activation of Saccharomyces cerevisiae OLE1 gene expression. Fatty acid-mediated regulation of Mga2p activity is independent of its proteolytic processing into a soluble transcription activator. J. Biol. Chem. 276, 43548–43556.10.1074/jbc.M107845200Search in Google Scholar

Coskun, U., Grzybek, M., Drechsel, D., and Simons, K. (2011). Regulation of human EGF receptor by lipids. Proc. Natl. Acad. Sci. USA 108, 9044–9048.10.1073/pnas.1105666108Search in Google Scholar

Cox, J.S., Shamu, C.E., and Walter, P. (1993). Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell 73, 1197–1206.10.1016/0092-8674(93)90648-ASearch in Google Scholar

Dowhan, W. and Bogdanov, M. (2009). Lipid-dependent membrane protein topogenesis. Annu. Rev. Biochem. 78, 515–540.10.1146/annurev.biochem.77.060806.091251Search in Google Scholar PubMed PubMed Central

Ejsing, C.S., Sampaio, J.L., Surendranath, V., Duchoslav, E., Ekroos, K., Klemm, R.W., Simons, K., and Shevchenko, A. (2009). Global analysis of the yeast lipidome by quantitative shotgun mass spectrometry. Proc. Natl. Acad. Sci. USA 106, 2136–2141.10.1073/pnas.0811700106Search in Google Scholar PubMed PubMed Central

Elbaz, Y. and Schuldiner, M. (2011). Staying in touch: the molecular era of organelle contact sites. Trends Biochem. Sci. 36, 616–623.10.1016/j.tibs.2011.08.004Search in Google Scholar PubMed

English, A.R. and Voeltz, G.K. (2013). Endoplasmic reticulum structure and interconnections with other organelles. Cold Spring Harb. Perspect. Biol. 5, a013227.10.1101/cshperspect.a013227Search in Google Scholar PubMed PubMed Central

Ernst, R., Mueller, B., Ploegh, H.L., and Schlieker, C. (2009). The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to facilitate protein dislocation from the ER. Mol. Cell 36, 28–38.10.1016/j.molcel.2009.09.016Search in Google Scholar PubMed PubMed Central

Ernst, R., Claessen, J.H., Mueller, B., Sanyal, S., Spooner, E., van der Veen, A.G., Kirak, O., Schlieker, C.D., Weihofen, W.A., and Ploegh, H.L. (2011). Enzymatic blockade of the ubiquitin-proteasome pathway. PLoS Biol. 8, e1000605.10.1371/journal.pbio.1000605Search in Google Scholar PubMed PubMed Central

Fei, W., Wang, H., Fu, X., Bielby, C., and Yang, H. (2009). Conditions of endoplasmic reticulum stress stimulate lipid droplet formation in Saccharomyces cerevisiae. Biochem. J. 424, 61–67.10.1042/BJ20090785Search in Google Scholar PubMed

Foresti, O., Ruggiano, A., Hannibal-Bach, H.K., Ejsing, C.S., and Carvalho, P. (2013). Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10/Teb4. eLife 2, e00953.10.7554/eLife.00953.015Search in Google Scholar

Fu, S., Yang, L., Li, P., Hofmann, O., Dicker, L., Hide, W., Lin, X., Watkins, S.M., Ivanov, A.R., and Hotamisligil, G.S. (2011). Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473, 528–531.10.1038/nature09968Search in Google Scholar PubMed PubMed Central

Goldstein, J.L., DeBose-Boyd, R.A., and Brown, M.S. (2006). Protein sensors for membrane sterols. Cell 124, 35–46.10.1016/j.cell.2005.12.022Search in Google Scholar PubMed

Grillitsch, K., Connerth, M., Kofeler, H., Arrey, T.N., Rietschel, B., Wagner, B., Karas, M., and Daum, G. (2011). Lipid particles/droplets of the yeast Saccharomyces cerevisiae revisited: lipidome meets proteome. Biochim. Biophys. Acta 1811, 1165–1176.10.1016/j.bbalip.2011.07.015Search in Google Scholar PubMed PubMed Central

Hammond, G.R., Fischer, M.J., Anderson, K.E., Holdich, J., Koteci, A., Balla, T., and Irvine, R.F. (2012). PI4P and PI(4,5)P2 are essential but independent lipid determinants of membrane identity. Science 337, 727–730.10.1126/science.1222483Search in Google Scholar PubMed PubMed Central

Hampton, R.Y., Gardner, R.G., and Rine, J. (1996). Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein. Mol. Biol. Cell 7, 2029–2044.10.1091/mbc.7.12.2029Search in Google Scholar PubMed PubMed Central

Han, X. and Gross, R.W. (2005). Shotgun lipidomics: electrospray ionization mass spectrometric analysis and quantitation of cellular lipidomes directly from crude extracts of biological samples. Mass Spectrom. Rev. 24, 367–412.10.1002/mas.20023Search in Google Scholar PubMed

Han, S., Lone, M.A., Schneiter, R., and Chang, A. (2010). Orm1 and Orm2 are conserved endoplasmic reticulum membrane proteins regulating lipid homeostasis and protein quality control. Proc. Natl. Acad. Sci. USA 107, 5851–5856.10.1073/pnas.0911617107Search in Google Scholar

Henry, S.A., Kohlwein, S.D., and Carman, G.M. (2012). Metabolism and regulation of glycerolipids in the yeast Saccharomyces cerevisiae. Genetics 190, 317–349.10.1534/genetics.111.130286Search in Google Scholar

Hoppe, T., Matuschewski, K., Rape, M., Schlenker, S., Ulrich, H.D., and Jentsch, S. (2000). Activation of a membrane-bound transcription factor by regulated ubiquitin/proteasome-dependent processing. Cell 102, 577–586.10.1016/S0092-8674(00)00080-5Search in Google Scholar

Jacquier, N., Choudhary, V., Mari, M., Toulmay, A., Reggiori, F., and Schneiter, R. (2011). Lipid droplets are functionally connected to the endoplasmic reticulum in Saccharomyces cerevisiae. J. Cell Sci. 124, 2424–2437.10.1242/jcs.076836Search in Google Scholar PubMed

Jonikas, M.C., Collins, S.R., Denic, V., Oh, E., Quan, E.M., Schmid, V., Weibezahn, J., Schwappach, B., Walter, P., Weissman, J.S., et al. (2009). Comprehensive characterization of genes required for protein folding in the endoplasmic reticulum. Science 323, 1693–1697.10.1126/science.1167983Search in Google Scholar PubMed PubMed Central

Kaiser, H.J., Orlowski, A., Rog, T., Nyholm, T.K., Chai, W., Feizi, T., Lingwood, D., Vattulainen, I., and Simons, K. (2011). Lateral sorting in model membranes by cholesterol-mediated hydrophobic matching. Proc. Natl. Acad. Sci. USA 108, 16628–16633.10.1073/pnas.1103742108Search in Google Scholar PubMed PubMed Central

Kandasamy, P., Vemula, M., Oh, C.S., Chellappa, R., and Martin, C.E. (2004). Regulation of unsaturated fatty acid biosynthesis in Saccharomyces: the endoplasmic reticulum membrane protein, Mga2p, a transcription activator of the OLE1 gene, regulates the stability of the OLE1 mRNA through exosome-mediated mechanisms. J. Biol. Chem. 279, 36586–36592.10.1074/jbc.M401557200Search in Google Scholar PubMed

Kim, H., Zhang, H., Meng, D., Russell, G., Lee, J.N., and Ye, J. (2013). UAS domain of Ubxd8 and FAF1 polymerizes upon interaction with long-chain unsaturated fatty acids. J. Lipid Res. 54, 2144–2152.10.1194/jlr.M037218Search in Google Scholar PubMed PubMed Central

Klemm, R.W., Ejsing, C.S., Surma, M.A., Kaiser, H.J., Gerl, M.J., Sampaio, J.L., de Robillard, Q., Ferguson, C., Proszynski, T.J., Shevchenko, A., et al. (2009). Segregation of sphingolipids and sterols during formation of secretory vesicles at the trans-Golgi network. J. Cell Biol. 185, 601–612.10.1083/jcb.200901145Search in Google Scholar PubMed PubMed Central

Klemm, E.J., Spooner, E., and Ploegh, H.L. (2011). Dual role of ancient ubiquitous protein 1 (AUP1) in lipid droplet accumulation and endoplasmic reticulum (ER) protein quality control. J. Biol. Chem. 286, 37602–37614.10.1074/jbc.M111.284794Search in Google Scholar PubMed PubMed Central

Klose, C., Surma, M.A., and Simons, K. (2013). Organellar lipidomics – background and perspectives. Curr. Opin. Cell Biol. 25, 406–413.10.1016/j.ceb.2013.03.005Search in Google Scholar PubMed

Kohlwein, S.D., Veenhuis, M., and van der Klei, I.J. (2013). Lipid droplets and peroxisomes: key players in cellular lipid homeostasis or a matter of fat – store ’em up or burn ’em down. Genetics 193, 1–50.10.1534/genetics.112.143362Search in Google Scholar PubMed PubMed Central

Kolawa, N.J., Sweredoski, M.J., Graham, R.L.J., Oania, R., Hess, S., and Deshaies, R.J. (2013). Perturbations to the ubiquitin conjugate proteome in yeast Δubx mutants identify Ubx2 as a regulator of membrane lipid composition. Mol. Cell Proteomics 12, 2791–2803.10.1074/mcp.M113.030163Search in Google Scholar PubMed PubMed Central

Korennykh, A. and Walter, P. (2012). Structural basis of the unfolded protein response. Annu. Rev. Cell Dev. Biol. 28, 251–277.10.1146/annurev-cellbio-101011-155826Search in Google Scholar PubMed

Krumpe, K., Frumkin, I., Herzig, Y., Rimon, N., Ozbalci, C., Brugger, B., Rapaport, D., and Schuldiner, M. (2012). Ergosterol content specifies targeting of tail-anchored proteins to mitochondrial outer membranes. Mol. Biol. Cell 23, 3927–3935.10.1091/mbc.e11-12-0994Search in Google Scholar

Lajoie, P., Moir, R.D., Willis, I.M., and Snapp, E.L. (2012). Kar2p availability defines distinct forms of endoplasmic reticulum stress in living cells. Mol. Biol. Cell 23, 955–964.10.1091/mbc.e11-12-0995Search in Google Scholar PubMed PubMed Central

Lee, J.N., Zhang, X., Feramisco, J.D., Gong, Y., and Ye, J. (2008). Unsaturated fatty acids inhibit proteasomal degradation of Insig-1 at a postubiquitination step. J. Biol. Chem. 283, 33772–33783.10.1074/jbc.M806108200Search in Google Scholar PubMed PubMed Central

Lee, J.N., Kim, H., Yao, H., Chen, Y., Weng, K., and Ye, J. (2010). Identification of Ubxd8 protein as a sensor for unsaturated fatty acids and regulator of triglyceride synthesis. Proc. Natl. Acad. Sci. USA 107, 21424–21429.10.1073/pnas.1011859107Search in Google Scholar PubMed PubMed Central

Lin, J.H., Walter, P., and Yen, T.S. (2008). Endoplasmic reticulum stress in disease pathogenesis. Annu. Rev. Pathol. 3, 399–425.10.1146/annurev.pathmechdis.3.121806.151434Search in Google Scholar PubMed PubMed Central

Listenberger, L.L., Han, X., Lewis, S.E., Cases, S., Farese, R.V., Jr., Ory, D.S., and Schaffer, J.E. (2003). Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc. Natl. Acad. Sci. USA 100, 3077–3082.10.1073/pnas.0630588100Search in Google Scholar PubMed PubMed Central

Loewen, C.J., Gaspar, M.L., Jesch, S.A., Delon, C., Ktistakis, N.T., Henry, S.A., and Levine, T.P. (2004). Phospholipid metabolism regulated by a transcription factor sensing phosphatidic acid. Science 304, 1644–1647.10.1126/science.1096083Search in Google Scholar PubMed

Martin, C.E., Oh, C.S., and Jiang, Y. (2007). Regulation of long chain unsaturated fatty acid synthesis in yeast. Biochim. Biophys. Acta 1771, 271–285.10.1016/j.bbalip.2006.06.010Search in Google Scholar PubMed

Meusser, B., Hirsch, C., Jarosch, E., and Sommer, T. (2005). ERAD: the long road to destruction. Nat. Cell Biol. 7, 766–772.10.1038/ncb0805-766Search in Google Scholar PubMed

Meyer, H., Bug, M., and Bremer, S. (2012). Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat. Cell Biol. 14, 117–123.10.1038/ncb2407Search in Google Scholar PubMed

Mitra, K., Ubarretxena-Belandia, I., Taguchi, T., Warren, G., and Engelman, D.M. (2004). Modulation of the bilayer thickness of exocytic pathway membranes by membrane proteins rather than cholesterol. Proc. Natl. Acad. Sci. USA 101, 4083–4088.10.1073/pnas.0307332101Search in Google Scholar PubMed PubMed Central

Mueller, B., Klemm, E.J., Spooner, E., Claessen, J.H., and Ploegh, H.L. (2008). SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins. Proc. Natl. Acad. Sci. USA 105, 12325–12330.10.1073/pnas.0805371105Search in Google Scholar PubMed PubMed Central

Needham, P.G. and Brodsky, J.L. (2013). How early studies on secreted and membrane protein quality control gave rise to the ER associated degradation (ERAD) pathway: the early history of ERAD. Biochim. Biophys. Acta 1833, 2447–2457.10.1016/j.bbamcr.2013.03.018Search in Google Scholar PubMed PubMed Central

Neuber, O., Jarosch, E., Volkwein, C., Walter, J., and Sommer, T. (2005). Ubx2 links the Cdc48 complex to ER-associated protein degradation. Nat. Cell Biol. 7, 993–998.10.1038/ncb1298Search in Google Scholar PubMed

Nilsson, I., Ohvo-Rekila, H., Slotte, J.P., Johnson, A.E., and von Heijne, G. (2001). Inhibition of protein translocation across the endoplasmic reticulum membrane by sterols. J. Biol. Chem. 276, 41748–41754.10.1074/jbc.M105823200Search in Google Scholar PubMed

Olzmann, J.A. and Kopito, R.R. (2011). Lipid droplet formation is dispensable for endoplasmic reticulum-associated degradation. J. Biol. Chem. 286, 27872–27874.10.1074/jbc.C111.266452Search in Google Scholar PubMed PubMed Central

Olzmann, J.A., Richter, C.M., and Kopito, R.R. (2013). Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet turnover. Proc. Natl. Acad. Sci. USA 110, 1345–1350.10.1073/pnas.1213738110Search in Google Scholar

Park, E. and Rapoport, T.A. (2012). Mechanisms of Sec61/SecY-mediated protein translocation across membranes. Annu. Rev. Biophys. 41, 21–40.10.1146/annurev-biophys-050511-102312Search in Google Scholar

Petschnigg, J., Wolinski, H., Kolb, D., Zellnig, G., Kurat, C.F., Natter, K., and Kohlwein, S.D. (2009). Good fat, essential cellular requirements for triacylglycerol synthesis to maintain membrane homeostasis in yeast. J. Biol. Chem. 284, 30981–30993.10.1074/jbc.M109.024752Search in Google Scholar

Piehler, J., Thomas, C., Garcia, K.C., and Schreiber, G. (2012). Structural and dynamic determinants of type I interferon receptor assembly and their functional interpretation. Immunol. Rev. 250, 317–334.10.1111/imr.12001Search in Google Scholar

Ploegh, H.L. (2007). A lipid-based model for the creation of an escape hatch from the endoplasmic reticulum. Nature 448, 435–438.10.1038/nature06004Search in Google Scholar

Promlek, T., Ishiwata-Kimata, Y., Shido, M., Sakuramoto, M., Kohno, K., and Kimata, Y. (2011). Membrane aberrancy and unfolded proteins activate the endoplasmic reticulum stress sensor Ire1 in different ways. Mol. Biol. Cell 22, 3520–3532.10.1091/mbc.e11-04-0295Search in Google Scholar

Radhakrishnan, A., Goldstein, J.L., McDonald, J.G., and Brown, M.S. (2008). Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance. Cell Metab. 8, 512–521.10.1016/j.cmet.2008.10.008Search in Google Scholar

Rape, M., Hoppe, T., Gorr, I., Kalocay, M., Richly, H., and Jentsch, S. (2001). Mobilization of processed, membrane-tethered SPT23 transcription factor by CDC48(UFD1/NPL4), a ubiquitin-selective chaperone. Cell 107, 667–677.10.1016/S0092-8674(01)00595-5Search in Google Scholar

Richly, H., Rape, M., Braun, S., Rumpf, S., Hoege, C., and Jentsch, S. (2005). A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting. Cell 120, 73–84.10.1016/j.cell.2004.11.013Search in Google Scholar PubMed

Rodriguez-Boulan, E. and Powell, S.K. (1992). Polarity of epithelial and neuronal cells. Annu. Rev. Cell Biol. 8, 395–427.10.1146/annurev.cb.08.110192.002143Search in Google Scholar PubMed

Sampaio, J.L., Gerl, M.J., Klose, C., Ejsing, C.S., Beug, H., Simons, K., and Shevchenko, A. (2011). Membrane lipidome of an epithelial cell line. Proc. Natl. Acad. Sci. USA 108, 1903–1907.10.1073/pnas.1019267108Search in Google Scholar

Schaffer, J.E. (2003). Lipotoxicity: when tissues overeat. Curr. Opin. Lipidol. 14, 281–287.10.1097/00041433-200306000-00008Search in Google Scholar

Schuberth, C. and Buchberger, A. (2005). Membrane-bound Ubx2 recruits Cdc48 to ubiquitin ligases and their substrates to ensure efficient ER-associated protein degradation. Nat. Cell Biol. 7, 999–1006.10.1038/ncb1299Search in Google Scholar

Schuck, S., Prinz, W.A., Thorn, K.S., Voss, C., and Walter, P. (2009). Membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response. J. Cell Biol. 187, 525–536.10.1083/jcb.200907074Search in Google Scholar

Schuldiner, M., Collins, S.R., Thompson, N.J., Denic, V., Bhamidipati, A., Punna, T., Ihmels, J., Andrews, B., Boone, C., Greenblatt, J.F., et al. (2005). Exploration of the function and organization of the yeast early secretory pathway through an epistatic miniarray profile. Cell 123, 507–519.10.1016/j.cell.2005.08.031Search in Google Scholar

Sharpe, H.J., Stevens, T.J., and Munro, S. (2010). A comprehensive comparison of transmembrane domains reveals organelle-specific properties. Cell 142, 158–169.10.1016/j.cell.2010.05.037Search in Google Scholar

Shcherbik, N. and Haines, D.S. (2007). Cdc48p(Npl4p/Ufd1p) binds and segregates membrane-anchored/tethered complexes via a polyubiquitin signal present on the anchors. Mol. Cell 25, 385–397.10.1016/j.molcel.2007.01.024Search in Google Scholar

Shcherbik, N., Zoladek, T., Nickels, J.T., and Haines, D.S. (2003). Rsp5p is required for ER bound Mga2p120 polyubiquitination and release of the processed/tethered transactivator Mga2p90. Curr. Biol. 13, 1227–1233.10.1016/S0960-9822(03)00457-3Search in Google Scholar

Shevchenko, A. and Simons, K. (2010). Lipidomics: coming to grips with lipid diversity. Nature Rev. Mol. Cell Biol. 11, 593–598.10.1038/nrm2934Search in Google Scholar PubMed

Shuai, K. and Liu, B. (2003). Regulation of JAK-STAT signalling in the immune system. Nat. Rev. Immunol. 3, 900–911.10.1038/nri1226Search in Google Scholar PubMed

Simons, K. and Gerl, M.J. (2010). Revitalizing membrane rafts: new tools and insights. Nature Rev. Mol. Cell Biol. 11, 688–699.10.1038/nrm2977Search in Google Scholar

Spandl, J., Lohmann, D., Kuerschner, L., Moessinger, C., and Thiele, C. (2011). Ancient ubiquitous protein 1 (AUP1) localizes to lipid droplets and binds the E2 ubiquitin conjugase G2 (Ube2g2) via its G2 binding region. J. Biol. Chem. 286, 5599–5606.10.1074/jbc.M110.190785Search in Google Scholar

Stolz, A., Hilt, W., Buchberger, A., and Wolf, D.H. (2011). Cdc48: a power machine in protein degradation. Trends Biochem. Sci. 36, 515–523.10.1016/j.tibs.2011.06.001Search in Google Scholar

Stukey, J.E., McDonough, V.M., and Martin, C.E. (1990). The OLE1 gene of Saccharomyces cerevisiae encodes the Δ9 fatty acid desaturase and can be functionally replaced by the rat stearoyl-CoA desaturase gene. J. Biol. Chem. 265, 20144–20149.10.1016/S0021-9258(17)30481-7Search in Google Scholar

Surma, M.A., Klose, C., Peng, D., Shales, M., Mrejen, C., Stefanko, A., Braberg, H., Gordon, D.E., Vorkel, D., Ejsing, C.S., et al. (2013). A lipid E-MAP identifies Ubx2 as a critical regulator of lipid saturation and lipid bilayer stress. Mol. Cell 51, 519–530.10.1016/j.molcel.2013.06.014Search in Google Scholar

Thibault, G., Shui, G., Kim, W., McAlister, G.C., Ismail, N., Gygi, S.P., Wenk, M.R., and Ng, D.T. (2012). The membrane stress response buffers lethal effects of lipid disequilibrium by reprogramming the protein homeostasis network. Mol. Cell 48, 16–27.10.1016/j.molcel.2012.08.016Search in Google Scholar

Thomas, C., Moraga, I., Levin, D., Krutzik, P.O., Podoplelova, Y., Trejo, A., Lee, C., Yarden, G., Vleck, S.E., Glenn, J.S., et al. (2011). Structural linkage between ligand discrimination and receptor activation by type I interferons. Cell 146, 621–632.10.1016/j.cell.2011.06.048Search in Google Scholar

van Meer, G., Voelker, D.R., and Feigenson, G.W. (2008). Membrane lipids: where they are and how they behave. Nat. Rev. Mol. Cell Biol. 9, 112–124.10.1038/nrm2330Search in Google Scholar

Varshavsky, A. (1997). The ubiquitin system. Trends Biochem. Sci. 22, 383–387.10.1016/S0968-0004(97)01122-5Search in Google Scholar

Volmer, R., van der Ploeg, K., and Ron, D. (2013). Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains. Proc. Natl. Acad. Sci. USA 110, 4628–4633.10.1073/pnas.1217611110Search in Google Scholar PubMed PubMed Central

von Heijne, G. (1989). Control of topology and mode of assembly of a polytopic membrane protein by positively charged residues. Nature 341, 456–458.10.1038/341456a0Search in Google Scholar PubMed

Walter, P. and Ron, D. (2011). The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081–1086.10.1126/science.1209038Search in Google Scholar PubMed

Wang, C.W. and Lee, S.C. (2012). The ubiquitin-like (UBX)-domain-containing protein Ubx2/Ubxd8 regulates lipid droplet homeostasis. J. Cell Sci. 125, 2930–2939.Search in Google Scholar

Wenk, M.R. (2005). The emerging field of lipidomics. Nat. Rev. Drug Discov. 4, 594–610.10.1038/nrd1776Search in Google Scholar PubMed

Werstuck, G.H., Lentz, S.R., Dayal, S., Hossain, G.S., Sood, S.K., Shi, Y.Y., Zhou, J., Maeda, N., Krisans, S.K., Malinow, M.R., et al. (2001). Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J. Clin. Invest. 107, 1263–1273.10.1172/JCI11596Search in Google Scholar PubMed PubMed Central

Xu, G., Sztalryd, C., Lu, X., Tansey, J.T., Gan, J., Dorward, H., Kimmel, A.R., and Londos, C. (2005). Post-translational regulation of adipose differentiation-related protein by the ubiquitin/proteasome pathway. J. Biol. Chem. 280, 42841–42847.10.1074/jbc.M506569200Search in Google Scholar PubMed

Yamamoto, K., Takahara, K., Oyadomari, S., Okada, T., Sato, T., Harada, A., and Mori, K. (2010). Induction of liver steatosis and lipid droplet formation in ATF6α-knockout mice burdened with pharmacological endoplasmic reticulum stress. Mol. Biol. Cell 21, 2975–2986.10.1091/mbc.e09-02-0133Search in Google Scholar

Received: 2013-7-31
Accepted: 2013-10-21
Published Online: 2013-10-23
Published in Print: 2014-03-01

©2014 by Walter de Gruyter Berlin Boston