A computational model of PKD and CERT interactions at the trans-Golgi network of mammalian cells

BMC Systems Biology

Nicole E Radde¹  Angelika Hausser²  Monilola A Olayioye²  Mariana Hornjik²  Patrick Weber¹ 

[1] Institute for Systems Theory and Automatic Control, University of Stuttgart, Pfaffenwaldring 9, Stuttgart 70569, Germany;Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart 70569, Germany

关键词: Trans-golgi network;    Bayesian inference;    CERT;    PKD;    Computational model;   

Others  :  1159568
DOI  :  10.1186/s12918-015-0147-1

 received in 2014-09-15, accepted in 2015-01-26,  发布年份 2015

【 摘 要 】

Background

In mammalian cells protein-lipid interactions at the trans-Golgi network (TGN) determine the formation of vesicles, which transfer secretory proteins to the cellular membrane. This process is regulated by a complex molecular network including protein kinase D (PKD), which is directly involved in the fission of transport vesicles, and its interaction with the ceramide transfer protein CERT that transports ceramide from the endoplasmic reticulum to the TGN.

Results

Here we present a novel quantitative kinetic model for the interactions of the key players PKD, phosphatidylinositol 4-kinase III beta (PI4KIII β) and CERT at the TGN membranes. We use sampling-based Bayesian analysis and perturbation experiments for model calibration and validation.

Conclusions

Our quantitative predictions of absolute molecular concentrations and reaction fluxes have major biological implications: Model comparison provides evidence that PKD and CERT interact in a cooperative manner to regulate ceramide transfer. Furthermore, we identify active PKD to be the dominant regulator of the network, especially of CERT-mediated ceramide transfer.

【 授权许可】

   
2015 Weber et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Mogelsvang S, Marsh BJ, Ladinsky MS, Howell KE: Predicting function from structure: 3D structure studies of the mammalian Golgi complex. Traffic 2004, 5(5):338-45. doi:10.1111/j.1398-9219.2004.00186.x
• [2]Hanada K, Kumagai K, Yasuda S, Miura Y, Kawano M, Fukasawa M, et al.: Molecular machinery for non-vesicular trafficking of ceramide. Nature 2003, 426(6968):803-9. doi:10.1038/nature02188
• [3]Bard F, Malhotra V: The formation of TGN-to-Plasma-Membrane transport carriers. Annu Rev Cell Dev Biol 2006, 22(1):439-55. doi:10.1146/annurev.cellbio.21.012704.133126. http://www.annualreviews.org/doi/pdf/10.1146/annurev.cellbio.21.012704.133126
• [4]Malhotra V, Campelo F: PKD regulates membrane fission to generate TGN to cell surface transport carriers. Cold Spring Harb Perspect Biol 2011, 3(2):a005280. doi:10.1101/cshperspect.a005280
• [5]Olayioye MA, Hausser A: Integration of non-vesicular and vesicular transport processes at the Golgi complex by the PKD-CERT network. Biochim Biophys Acta 2012, 1821(8):1096-103. doi:10.1016/j.bbalip.2011.12.005
• [6]Hanada K: Intracellular trafficking of ceramide by ceramide transfer protein. Proc Jpn Acad Ser B Phys Biol Sci 2010, 86:426-37.
• [7]Hausser A, Storz P, Märtens S, Link G, Toker A, Pfizenmaier K: Protein kinase D regulates vesicular transport by phosphorylating and activating phosphatidylinositol-4 kinase IIIbeta at the Golgi complex. Nat Cell Biol 2005, 7(9):880-6. doi:10.1038/ncb1289
• [8]Tóth B, Balla A, Ma H, Knight ZA, Shokat KM, Balla T: Phosphatidylinositol 4-kinase III β regulates the transport of ceramide between the endoplasmic reticulum and Golgi. J Biol Chem 2006, 281(47):36369-77. doi:10.1074/jbc.M604935200
• [9]D’Angelo G, Vicinanza M, Campli AD, Matteis MAD: The multiple roles of PtdIns(4)P – not just the precursor of PtdIns(4,5)P2. J Cell Sci 2008, 121(Pt 12):1955-63. doi:10.1242/jcs.023630
• [10]Hanada K: Discovery of the molecular machinery CERT for endoplasmic reticulum-to-Golgi trafficking of ceramide. Mol Cell Biochem 2006, 286(1–2):23-31. doi:10.1007/s11010-005-9044-z
• [11]Hanada K, Kumagai K, Tomishige N, Kawano M: CERT and intracellular trafficking of ceramide. Biochim Biophys Acta 2007, 1771(6):644-53. doi:10.1016/j.bbalip.2007.01.009
• [12]Hanada K, Kumagai K, Tomishige N, Yamaji T: CERT-mediated trafficking of ceramide. Biochim Biophys Acta 2009, 1791(7):684-91. doi:10.1016/j.bbalip.2009.01.006
• [13]Perry RJ, Ridgway ND: Molecular mechanisms and regulation of ceramide transport. Biochim Biophys Acta 2005, 1734(3):220-34. doi:10.1016/j.bbalip.2005.04.001
• [14]Huitema K, van den Dikkenberg J, Brouwers JFHM, Holthuis JCM: Identification of a family of animal sphingomyelin synthases. EMBO J 2004, 23(1):33-44. doi:10.1038/sj.emboj.7600034
• [15]Tafesse FG, Ternes P, Holthuis JCM: The multigenic sphingomyelin synthase family. J Biol Chem 2006, 281(40):29421-25. doi:10.1074/jbc.R600021200
• [16]Tafesse FG, Huitema K, Hermansson M, van der Poel S, van den Dikkenberg J, Uphoff A, et al.: Both sphingomyelin synthases SMS1 and SMS2 are required for sphingomyelin homeostasis and growth in human HeLa cells. J Biol Chem 2007, 282(24):17537-47. doi:10.1074/jbc.M702423200
• [17]Maeda Y, Beznoussenko GV, Lint JV, Mironov AA, Malhotra V: Recruitment of protein kinase D to the trans-Golgi network via the first cysteine-rich domain. EMBO J 2001, 20(21):5982-90. doi:10.1093/emboj/20.21.5982
• [18]Baron CL, Malhotra V: Role of diacylglycerol in PKD recruitment to the TGN and protein transport to the plasma membrane. Science 2002, 295(5553):325-8. doi:10.1126/science.1066759
• [19]Añel AMD, Malhotra V: PKCeta is required for β1γ2/ β3γ2- and PKD-mediated transport to the cell surface and the organization of the Golgi apparatus. J Cell Biol 2005, 169(1):83-91. doi:10.1083/jcb.200412089
• [20]Fugmann T, Hausser A, Schöffler P, Schmid S, Pfizenmaier K, Olayioye MA: Regulation of secretory transport by protein kinase D-mediated phosphorylation of the Ceramide Transfer Protein. J Cell Biol 2007, 178:15-22.
• [21]Tomishige N, Kumagai K, Kusuda J, Nishijima M, Hanada K: Casein kinase I gamma 2 down-regulates trafficking of ceramide in the synthesis of sphingomyelin. Mol Biol Cell 2009, 20(1):348-57. doi:10.1091/mbc.E08-07-0669
• [22]Kumagai K, Kawano M, Shinkai-Ouchi F, Nishijima M, Hanada K: Interorganelle trafficking of ceramide is regulated by phosphorylation-dependent cooperativity between the PH and START domains of CERT. J Biol Chem 2007, 282(24):17758-66. doi:10.1074/jbc.M702291200
• [23]Saito S, Matsui H, Kawano M, Kumagai K, Tomishige N, Hanada K, et al.: Protein phosphatase 2C ε is an endoplasmic reticulum integral membrane protein that dephosphorylates the ceramide transport protein CERT to enhance its association with organelle membranes. J Biol Chem 2008, 283(10):6584-93. doi:10.1074/jbc.M707691200
• [24]Hirschberg K, Miller CM, Ellenberg J, Presley JF, Siggia ED, Phair RD, et al.: Kinetic analysis of secretory protein traffic and characterization of Golgi to plasma membrane transport intermediates in living cells. J Cell Biol 1998, 143(6):1485-503.
• [25]Corda D, Carcedo CH, Bonazzi M, Luini A, Spanò S: Molecular aspects of membrane fission in the secretory pathway. Cell Mol Life Sci 2002, 59(11):1819-32.
• [26]Shemesh T, Luini A, Malhotra V, Burger KNJ, Kozlov MM: Prefission constriction of Golgi tubular carriers driven by local lipid metabolism: a theoretical model. Biophys J 2003, 85(6):3813-27. doi:10.1016/S0006-3495(03)74796-1
• [27]Thomaseth C, Weber P, Hamm T, Kashima K, Radde N: Modeling sphingomyelin synthase 1 driven reaction at the Golgi apparatus can explain data by inclusion of a positive feedback mechanism. J Theor Biol 2013, 337:174-80. doi:10.1016/j.jtbi.2013.08.022
• [28]Florin L, Pegel A, Becker E, Hausser A, Olayioye MA, Kaufmann H: Heterologous expression of the lipid transfer protein CERT increases therapeutic protein productivity of mammalian cells. J Biotechnol 2009, 141:84-90. doi:10.1016/j.jbiotec.2009.02.014
• [29]Gelman A, Carlin JB, Stern HS, Rubin DB: Bayesian Data Analysis, 2nd edn. Texts in Statistical Science. Chapman & Hall, CRC, Boca Raton, London, NewYork, Washington D.C; 2004.
• [30]Gutenkunst RN, Waterfall JJ, Casey FP, Brown KS, Myers CR, Sethna JP: Universally sloppy parameter sensitivities in systems biology models. PLoS Comp Biol 2007, 3(10):1871-78.
• [31]Eydgahi H, Chen WW, Muhlich JL, Vitkup D, Tsitsiklis JN, Sorger PK: Properties of cell death models calibrated and compared using Bayesian approaches. Mol Syst Biol 2013, 9(644):644.
• [32]Hausser A, Link G, Bamberg L, Burzlaff A, Lutz S, Pfizenmaier K, et al.: Structural requirements for localization and activation of protein kinase C mu (PKC mu) at the Golgi compartment. J Cell Biol 2002, 156(1):65-74. doi:10.1083/jcb.200110047
• [33]Huck B, Kemkemer R, Franz-Wachtel M, Macek B, Hausser A, Olayioye MA: GIT1 phosphorylation on serine 46 by PKD3 regulates paxillin trafficking and cellular protrusive activity. J Biol Chem 2012, 287(41):34604-13. doi:10.1074/jbc.M112.374652
• [34]Gassmann M, Grenacher B, Rohde B, Vogel J: Quantifying western blots: pitfalls of densitometry. Electrophoresis 2009, 30(11):1845-55. doi:10.1002/elps.200800720
• [35]Schmidt H, Jirstrand M: Systems biology toolbox for matlab: a computational platform for research in systems biology. Bioinformatics 2006, 22(4):514-5. doi:10.1093/bioinformatics/bti799. http://bioinformatics.oxfordjournals.org/cgi/reprint/22/4/514.pdf
• [36]Cohen S, Hindmarsh C: Cvode, A Stiff/nonstiff Ode Solver In C. Comput Phys 1996, 10(2):138-43.
• [37]Calderhead B, Girolami M: Estimating bayes factors via thermodynamic integration and population mcmc. Comput Stat Data Anal 2009, 53:4028-45.
• [38]Gelman A, Rubin DB: Inference from iterative simulation using multiple sequences. Stat Sci 1992, 7(4):457-72.
• [39]Kawano M, Kumagai K, Nishijima M, Hanada K: Efficient trafficking of ceramide from the endoplasmic reticulum to the Golgi apparatus requires a vamp-associated protein-interacting ffat motif of cert. J Biol Chem 2006, 281(40):30279-88. doi:10.1074/jbc.M605032200
• [40]Kreutz C, Timmer J: Systems biology: experimental design. FEBS J 2009, 276(4):923-42. doi:10.1111/j.1742-4658.2008.06843.x
• [41]Chiu T, Rozengurt E: PKD in intestinal epithelial cells: rapid activation by phorbol esters, LPA, and angiotensin through PKC. Am J Physiol Cell Physiol 2001, 280(4):929-42.
• [42]Bravo-Altamirano K, George KM, Frantz M-C, Lavalle CR, Tandon M, Leimgruber S, et al.: Synthesis and structure-activity relationships of benzothienothiazepinone inhibitors of protein kinase D. ACS Med Chem Lett 2011, 2(2):154-9. doi:10.1021/ml100230n
• [43]Weber P, Kramer A, Dingler C, Radde N: Trajectory-oriented bayesian experiment design versus Fisher A-optimal design: an in depth comparison study. Bioinformatics 2012, 28(18):535-41. doi:10.1093/bioinformatics/bts377. http://bioinformatics.oxfordjournals.org/content/28/18/i535.full.pdf+html
• [44]Kass RE, Raftery AE: Bayes factors. J Am Stat Assoc 1995, 90(430):773-95.
• [45]Tan CW, Gardiner BS, Hirokawa Y, Layton MJ, Smith DW, Burgess AW: Wnt signalling pathway parameters for mammalian cells. PLoS One 2012, 7(2):31882. doi:10.1371/journal.pone.0031882
• [46]Díaz Añel AM: Phospholipase c beta3 is a key component in the gbetagamma/pkceta/pkd-mediated regulation of trans-Golgi network to plasma membrane transport. Biochem J 2007, 406(1):157-65. doi:10.1042/BJ20070359
• [47]Sarri E, Sicart A, Lázaro-Diéguez F, Egea G: Phospholipid synthesis participates in the regulation of diacylglycerol required for membrane trafficking at the Golgi complex. J Biol Chem 2011, 286(32):28632-43. doi:10.1074/jbc.M111.267534
• [48]Eden E, Geva-Zatorsky N, Issaeva I, Cohen A, Dekel E, Danon T, et al.: Proteome half-life dynamics in living human cells. Science 2011, 331(6018):764-8. doi:10.1126/science.1199784
• [49]Finka A, Goloubinoff P: Proteomic data from human cell cultures refine mechanisms of chaperone-mediated protein homeostasis. Cell Stress Chaperones 2013, 18(5):591-605. doi:10.1007/s12192-013-0413-3
• [50]Kumagai K, Kawano-Kawada M, Hanada K: Phosphoregulation of the ceramide transport protein cert at serine 315 in the interaction with vamp-associated protein (vap) for inter-organelle trafficking of ceramide in mammalian cells. J Biol Chem 2014, 289(15):10748-60. doi:10.1074/jbc.M113.528380
• [51]Lev S: Lipid homoeostasis and Golgi secretory function. Biochem Soc Trans 2006, 34(Pt 3):363-6. doi:10.1042/BST0340363
• [52]Nhek S, Ngo M, Yang X, Ng MM, Field SJ, Asara JM, et al.: Regulation of osbp Golgi localization through protein kinase d-mediated phosphorylation. Mol Biol Cell 2010, 21:2327-2337. doi:10.1091/mbc.E10-02-0090