All about that fat: Lipid modification of proteins in Cryptococcus neoformans

详细信息    查看全文

• 作者：Felipe H. Santiago-Tirado ; Tamara L. Doering
• 关键词：Cryptococcus ; palmitoylation ; myristoylation ; prenylation ; isoprenylation ; GPI ; anchored proteins ; lipid modification ; protein lipidation
• 刊名：Journal of Microbiology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：54
• 期：3
• 页码：212-222
• 全文大小：784 KB
• 参考文献：Aitken, A., Cohen, P., Santikarn, S., Williams, D.H., Calder, A.G., Smith, A., and Klee, C.B. 1982. Identification of the NH2-terminal blocking group of calcineurin B as myristic acid. FEBS Lett. 150, 314–318.CrossRef PubMed
  Blanc, M., Blaskovic, S., and van der Goot, F.G. 2013. Palmitoylation, pathogens and their host. Biochem. Soc. Trans. 41, 84–88.CrossRef PubMed
  Brown, G.D., Denning, D.W., Gow, N.A., Levitz, S.M., Netea, M.G., and White, T.C. 2012. Hidden killers: human fungal infections. Sci. Transl. Med. 4, 165rv113.CrossRef
  Caminero, A., Calvo, E., Valentin, E., Ruiz-Herrera, J., Lopez, J.A., and Sentandreu, R. 2014. Identification of Candida albicans wall mannoproteins covalently linked by disulphide and/or alkalisensitive bridges. Yeast 31, 137–144.CrossRef PubMed
  Chayakulkeeree, M., Sorrell, T.C., Siafakas, A.R., Wilson, C.F., Pantarat, N., Gerik, K.J., Boadle, R., and Djordjevic, J.T. 2008. Role and mechanism of phosphatidylinositol-specific phospholipase C in survival and virulence of Cryptococcus neoformans. Mol. Microbiol. 69, 809–826.PubMed
  Costachel, C., Coddeville, B., Latge, J.P., and Fontaine, T. 2005. Glycosylphosphatidylinositol-anchored fungal polysaccharide in Aspergillus fumigatus. J. Biol. Chem. 280, 39835–39842.CrossRef PubMed
  Das, U., Kumar, S., Dimmock, J.R., and Sharma, R.K. 2012. Inhibition of protein N-myristoylation: a therapeutic protocol in developing anticancer agents. Curr. Cancer Drug Target 12, 667–692.CrossRef
  Davidson, R.C., Moore, T.D., Odom, A.R., and Heitman, J. 2000. Characterization of the MFalpha pheromone of the human fungal pathogen Cryptococcus neoformans. Mol. Microbiol. 38, 1017–1026.CrossRef PubMed
  Djordjevic, J.T., Del Poeta, M., Sorrell, T.C., Turner, K.M., and Wright, L.C. 2005. Secretion of cryptococcal phospholipase B1 (PLB1) is regulated by a glycosylphosphatidylinositol (GPI) anchor. Biochem. J. 389, 803–812.PubMedCentral CrossRef PubMed
  Doering, T.L. 2009. How sweet it is! Cell wall biogenesis and polysaccharide capsule formation in Cryptococcus neoformans. Annu. Rev. Microbiol. 63, 223–247.PubMedCentral CrossRef PubMed
  Duronio, R.J., Reed, S.I., and Gordon, J.I. 1992. Mutations of human myristoyl-CoA:protein N-myristoyltransferase cause temperature- sensitive myristic acid auxotrophy in Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA 89, 4129–4133.PubMedCentral CrossRef PubMed
  Eastman, R.T., Buckner, F.S., Yokoyama, K., Gelb, M.H., and Van Voorhis, W.C. 2006. Thematic review series: lipid posttranslational modifications. Fighting parasitic disease by blocking protein farnesylation. J. Lipid Res. 47, 233–240.CrossRef PubMed
  Eichler, J. and Adams, M.W. 2005. Posttranslational protein modification in Archaea. Microbiol. Mol. Biol. Rev. 69, 393–425.PubMedCentral CrossRef PubMed
  Eigenheer, R.A., Jin Lee, Y., Blumwald, E., Phinney, B.S., and Gelli, A. 2007. Extracellular glycosylphosphatidylinositol-anchored mannoproteins and proteases of Cryptococcus neoformans. FEMS Yeast Res. 7, 499–510.CrossRef PubMed
  Fang, W., Robinson, D.A., Raimi, O.G., Blair, D.E., Harrison, J.R., Lockhart, D.E., Torrie, L.S., Ruda, G.F., Wyatt, P.G., Gilbert, I.H., et al. 2015. N-myristoyltransferase is a cell wall target in Aspergillus fumigatus. ACS Chem. Biol. 10, 1425–1434.PubMedCentral CrossRef PubMed
  Ferguson, M.A., Low, M.G., and Cross, G.A. 1985. Glycosyl-sn-1,2- dimyristylphosphatidylinositol is covalently linked to Trypanosoma brucei variant surface glycoprotein. J. Biol. Chem. 260, 14547–14555.
  Folch, J. and Lees, M. 1951. Proteolipides, a new type of tissue lipoproteins; their isolation from brain. J. Biol. Chem. 191, 807–817.PubMed
  Fontaine, T., Magnin, T., Melhert, A., Lamont, D., Latge, J.P., and Ferguson, M.A. 2003. Structures of the glycosylphosphatidylinositol membrane anchors from Aspergillus fumigatus membrane proteins. Glycobiology 13, 169–177.CrossRef PubMed
  Fortwendel, J.R., Juvvadi, P.R., Rogg, L.E., Asfaw, Y.G., Burns, K.A., Randell, S.H., and Steinbach, W.J. 2012. Plasma membrane localization is required for RasA-mediated polarized morphogenesis and virulence of Aspergillus fumigatus. Eukaryot. Cell 11, 966–977.PubMedCentral CrossRef PubMed
  Franzot, S.P. and Doering, T.L. 1999. Inositol acylation of glycosylphosphatidylinositols in the pathogenic fungus Cryptococcus neoformans and the model yeast Saccharomyces cerevisiae. Biochem. J. 340(Pt 1), 25–32.PubMedCentral PubMed
  Frenal, K., Tay, C.L., Mueller, C., Bushell, E.S., Jia, Y., Graindorge, A., Billker, O., Rayner, J.C., and Soldati-Favre, D. 2013. Global analysis of apicomplexan protein S-acyl transferases reveals an enzyme essential for invasion. Traffic 14, 895–911.PubMedCentral CrossRef PubMed
  Frieman, M.B. and Cormack, B.P. 2004. Multiple sequence signals determine the distribution of glycosylphosphatidylinositol proteins between the plasma membrane and cell wall in Saccharomyces cerevisiae. Microbiology 150, 3105–3114.CrossRef PubMed
  Georgopapadakou, N.H. 2002. Antifungals targeted to protein modification: focus on protein N-myristoyltransferase. Expert. Opin. Investig. Drugs 11, 1117–1125.CrossRef PubMed
  Gilbert, N.M., Baker, L.G., Specht, C.A., and Lodge, J.K. 2012. A glycosylphosphatidylinositol anchor is required for membrane localization but dispensable for cell wall association of chitin deacetylase 2 in Cryptococcus neoformans. mBio 3, e00007–12.PubMedCentral CrossRef PubMed
  Gillingham, A.K. and Munro, S. 2007. The small G proteins of the Arf family and their regulators. Annu. Rev. Cell. Dev. Biol. 23, 579–611.CrossRef PubMed
  Goldston, A.M., Sharma, A.I., Paul, K.S., and Engman, D.M. 2014. Acylation in trypanosomatids: an essential process and potential drug target. Trends Parasitol. 30, 350–360.PubMedCentral CrossRef PubMed
  Gutkowska, M. and Swiezewska, E. 2012. Structure, regulation and cellular functions of Rab geranylgeranyl transferase and its cellular partner Rab Escort Protein. Mol. Membr. Biol. 29, 243–256.CrossRef PubMed
  Hast, M.A., Nichols, C.B., Armstrong, S.M., Kelly, S.M., Hellinga, H.W., Alspaugh, J.A., and Beese, L.S. 2011. Structures of Cryptococcus neoformans protein farnesyltransferase reveal strategies for developing inhibitors that target fungal pathogens. J. Biol. Chem. 286, 35149–35162.PubMedCentral CrossRef PubMed
  Hicks, S.W. and Galan, J.E. 2013. Exploitation of eukaryotic subcellular targeting mechanisms by bacterial effectors. Nat. Rev. Microbiol. 11, 316–326.CrossRef PubMed
  Honscher, C. and Ungermann, C. 2014. A close-up view of membrane contact sites between the endoplasmic reticulum and the endolysosomal system: from yeast to man. Crit. Rev. Biochem. Mol. Biol. 49, 262–268.CrossRef PubMed
  Howie, J., Reilly, L., Fraser, N.J., Vlachaki Walker, J.M., Wypijewski, K.J., Ashford, M.L., Calaghan, S.C., McClafferty, H., Tian, L., Shipston, M.J., et al. 2014. Substrate recognition by the cell surface palmitoyl transferase DHHC5. Proc. Natl. Acad. Sci. USA 111, 17534–17539.PubMedCentral CrossRef PubMed
  Ivanov, S.S. and Roy, C. 2013. Host lipidation: a mechanism for spatial regulation of Legionella effectors. Curr. Top. Microbiol. Immunol. 376, 135–154.PubMed
  Janbon, G., Ormerod, K.L., Paulet, D., Byrnes, E.J., 3rd, Yadav, V., Chatterjee, G., Mullapudi, N., Hon, C.C., Billmyre, R.B., Brunel, F., et al. 2014. Analysis of the genome and transcriptome of Cryptococcus neoformans var. grubii reveals complex RNA expression and microevolution leading to virulence attenuation. PLoS Genet. 10, e1004261.PubMedCentral CrossRef PubMed
  Jones, M.L., Collins, M.O., Goulding, D., Choudhary, J.S., and Rayner, J.C. 2012. Analysis of protein palmitoylation reveals a pervasive role in Plasmodium development and pathogenesis. Cell Host Microbe 12, 246–258.PubMedCentral CrossRef PubMed
  Kamiya, Y., Sakurai, A., Tamura, S., and Takahashi, N. 1978. Structure of rhodotorucine A, a novel lipopeptide, inducing mating tube formation in Rhodosporidium toruloides. Biochem. Biophys. Res. Commun. 83, 1077–1083.CrossRef PubMed
  Kempf, M., Cottin, J., Licznar, P., Lefrancois, C., Robert, R., and Apaire-Marchais, V. 2009. Disruption of the GPI protein-encoding gene IFF4 of Candida albicans results in decreased adherence and virulence. Mycopathologia 168, 73–77.CrossRef PubMed
  Lam, K.K., Davey, M., Sun, B., Roth, A.F., Davis, N.G., and Conibear, E. 2006. Palmitoylation by the DHHC protein Pfa4 regulates the ER exit of Chs3. J. Cell. Biol. 174, 19–25.PubMedCentral CrossRef PubMed
  Langner, C.A., Lodge, J.K., Travis, S.J., Caldwell, J.E., Lu, T., Li, Q., Bryant, M.L., Devadas, B., Gokel, G.W., Kobayashi, G.S., and et al. 1992. 4-oxatetradecanoic acid is fungicidal for Cryptococcus neoformans and inhibits replication of human immunodeficiency virus I. J. Biol. Chem. 267, 17159–17169.PubMed
  Lin, X., Hull, C.M., and Heitman, J. 2005. Sexual reproduction between partners of the same mating type in Cryptococcus neoformans. Nature 434, 1017–1021.CrossRef PubMed
  Lin, X., Jackson, J.C., Feretzaki, M., Xue, C., and Heitman, J. 2010. Transcription factors Mat2 and Znf2 operate cellular circuits orchestrating opposite- and same-sex mating in Cryptococcus neoformans. PLoS Genet. 6, e1000953.PubMedCentral CrossRef PubMed
  Lobo, S., Greentree, W.K., Linder, M.E., and Deschenes, R.J. 2002. Identification of a Ras palmitoyltransferase in Saccharomyces cerevisiae. J. Biol. Chem. 277, 41268–41273.CrossRef PubMed
  Lodge, J.K., Jackson-Machelski, E., Higgins, M., McWherter, C.A., Sikorski, J.A., Devadas, B., and Gordon, J.I. 1998. Genetic and biochemical studies establish that the fungicidal effect of a fully depeptidized inhibitor of Cryptococcus neoformans myristoyl- CoA:protein N-myristoyltransferase (Nmt) is Nmt-dependent. J. Biol. Chem. 273, 12482–12491.CrossRef PubMed
  Lodge, J.K., Jackson-Machelski, E., Toffaletti, D.L., Perfect, J.R., and Gordon, J.I. 1994a. Targeted gene replacement demonstrates that myristoyl-CoA: protein N-myristoyltransferase is essential for viability of Cryptococcus neoformans. Proc. Natl. Acad. Sci. USA 91, 12008–12012.PubMedCentral CrossRef PubMed
  Lodge, J.K., Johnson, R.L., Weinberg, R.A., and Gordon, J.I. 1994b. Comparison of myristoyl-CoA:protein N-myristoyltransferases from three pathogenic fungi: Cryptococcus neoformans, Histoplasma capsulatum, and Candida albicans. J. Biol. Chem. 269, 2996–3009.PubMed
  Loftus, B.J., Fung, E., Roncaglia, P., Rowley, D., Amedeo, P., Bruno, D., Vamathevan, J., Miranda, M., Anderson, I.J., Fraser, J.A., et al. 2005. The genome of the basidiomycetous yeast and human pathogen Cryptococcus neoformans. Science 307, 1321–1324.PubMedCentral CrossRef PubMed
  McClelland, C.M., Fu, J., Woodlee, G.L., Seymour, T.S., and Wickes, B.L. 2002. Isolation and characterization of the Cryptococcus neoformans MATa pheromone gene. Genetics 160, 935–947.PubMedCentral PubMed
  McLellan, C.A., Whitesell, L., King, O.D., Lancaster, A.K., Mazitschek, R., and Lindquist, S. 2012. Inhibiting GPI anchor biosynthesis in fungi stresses the endoplasmic reticulum and enhances immunogenicity. ACS Chem. Biol. 7, 1520–1528.CrossRef PubMed
  Menon, A.K. 2008. Chapter 2: Lipid Modifications of Proteins, pp. xii, 631. In Vance, D.E. and Vance, J.E. (eds.), Biochemistry of lipids, lipoproteins and membranes. Elsevier, Amsterdam; Boston.
  Michaelis, S. and Barrowman, J. 2012. Biogenesis of the Saccharomyces cerevisiae pheromone a-factor, from yeast mating to human disease. Microbiol. Mol. Biol. Rev. 76, 626–651.PubMedCentral CrossRef PubMed
  Miura, G.I. and Treisman, J.E. 2006. Lipid modification of secreted signaling proteins. Cell Cycle 5, 1184–1188.PubMedCentral CrossRef PubMed
  Moissoglu, K. and Schwartz, M.A. 2014. Spatial and temporal control of Rho GTPase functions. Cell Logist. 4, e943618.PubMedCentral CrossRef PubMed
  Muñiz, M. and Zurzolo, C. 2014. Sorting of GPI-anchored proteins from yeast to mammals—common pathways at different sites? J. Cell. Sci. 127, 2793–2801.CrossRef PubMed
  Nakayama, H., Kurokawa, K., and Lee, B.L. 2012. Lipoproteins in bacteria: structures and biosynthetic pathways. FEBS J. 279, 4247–4268.CrossRef PubMed
  Nguyen, U.T., Goody, R.S., and Alexandrov, K. 2010. Understanding and exploiting protein prenyltransferases. Chembiochem 11, 1194–1201.CrossRef PubMed
  Nichols, C.B., Ferreyra, J., Ballou, E.R., and Alspaugh, J.A. 2009. Subcellular localization directs signaling specificity of the Cryptococcus neoformans Ras1 protein. Eukaryot. Cell 8, 181–189.PubMedCentral CrossRef PubMed
  Nichols, C.B., Ost, K.S., Grogan, D.P., Pianalto, K., Hasan, S., and Alspaugh, J.A. 2015. Impact of protein palmitoylation on the virulence potential of Cryptococcus neoformans. Eukaryot. Cell 14, 626–635.PubMedCentral CrossRef PubMed
  Ohno, Y., Kashio, A., Ogata, R., Ishitomi, A., Yamazaki, Y., and Kihara, A. 2012. Analysis of substrate specificity of human DHHC protein acyltransferases using a yeast expression system. Mol. Biol. Cell 23, 4543–4551.PubMedCentral CrossRef PubMed
  Ohno, Y., Kihara, A., Sano, T., and Igarashi, Y. 2006. Intracellular localization and tissue-specific distribution of human and yeast DHHC cysteine-rich domain-containing proteins. Biochim. Biophys. Acta. 1761, 474–483.CrossRef PubMed
  Orlean, P. and Menon, A.K. 2007. Thematic review series: lipid posttranslational modifications. GPI anchoring of protein in yeast and mammalian cells, or: how we learned to stop worrying and love glycophospholipids. J. Lipid Res. 48, 993–1011.CrossRef PubMed
  Panackal, A.A., Wuest, S.C., Lin, Y.C., Wu, T., Zhang, N., Kosa, P., Komori, M., Blake, A., Browne, S.K., Rosen, L.B., et al. 2015. Paradoxical immune responses in non-hiv cryptococcal meningitis. PLoS Pathog. 11, e1004884.PubMedCentral CrossRef PubMed
  Panethymitaki, C., Bowyer, P.W., Price, H.P., Leatherbarrow, R.J., Brown, K.A., and Smith, D.F. 2006. Characterization and selective inhibition of myristoyl-CoA:protein N-myristoyltransferase from Trypanosoma brucei and Leishmania major. Biochem. J. 396, 277–285.PubMedCentral CrossRef PubMed
  Park, B.J., Wannemuehler, K.A., Marston, B.J., Govender, N., Pappas, P.G., and Chiller, T.M. 2009. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 23, 525–530.CrossRef PubMed
  Piispanen, A.E., Bonnefoi, O., Carden, S., Deveau, A., Bassilana, M., and Hogan, D.A. 2011. Roles of Ras1 membrane localization during Candida albicans hyphal growth and farnesol response. Eukaryot. Cell 10, 1473–1484.PubMedCentral CrossRef PubMed
  Richard, M., Ibata-Ombetta, S., Dromer, F., Bordon-Pallier, F., Jouault, T., and Gaillardin, C. 2002. Complete glycosylphosphatidylinositol anchors are required in Candida albicans for full morphogenesis, virulence and resistance to macrophages. Mol. Microbiol. 44, 841–853.CrossRef PubMed
  Roth, A.F., Feng, Y., Chen, L., and Davis, N.G. 2002. The yeast DHHC cysteine-rich domain protein Akr1p is a palmitoyl transferase. J. Cell. Biol. 159, 23–28.PubMedCentral CrossRef PubMed
  Roth, A.F., Wan, J., Bailey, A.O., Sun, B., Kuchar, J.A., Green, W.N., Phinney, B.S., Yates, J.R.3rd, and Davis, N.G. 2006. Global analysis of protein palmitoylation in yeast. Cell 125, 1003–1013.PubMedCentral CrossRef PubMed
  Sanchez-Mir, L., Franco, A., Martin-Garcia, R., Madrid, M., Vicente- Soler, J., Soto, T., Gacto, M., Perez, P., and Cansado, J. 2014. Rho2 palmitoylation is required for plasma membrane localization and proper signaling to the fission yeast cell integrity mitogen-activated protein kinase pathway. Mol. Cell. Biol. 34, 2745–2759.PubMedCentral CrossRef PubMed
  Santiago-Tirado, F.H., Peng, T., Yang, M., Hang, H.C., and Doering, T.L. 2015. A single protein s-acyl transferase acts through diverse substrates to determine cryptococcal morphology, stress tolerance, and pathogenic outcome. PLoS Pathog. 11, e1004908.PubMedCentral CrossRef PubMed
  Schmidt, M.F., Bracha, M., and Schlesinger, M.J. 1979. Evidence for covalent attachment of fatty acids to Sindbis virus glycoproteins. Proc. Natl. Acad. Sci. USA 76, 1687–1691.PubMedCentral CrossRef PubMed
  Selvig, K., Ballou, E.R., Nichols, C.B., and Alspaugh, J.A. 2013. Restricted substrate specificity for the geranylgeranyltransferase-I enzyme in Cryptococcus neoformans: implications for virulence. Eukaryot. Cell 12, 1462–1471.PubMedCentral CrossRef PubMed
  Shen, H., Chen, S.M., Liu, W., Zhu, F., He, L.J., Zhang, J.D., Zhang, S.Q., Yan, L., Xu, Z., Xu, G.T., et al. 2015a. Abolishing cell wall glycosylphosphatidylinositol-anchored proteins in Candida albicans enhances recognition by host dectin-1. Infect. Immun. 83, 2694–2704.PubMedCentral CrossRef PubMed
  Shen, W.C., Davidson, R.C., Cox, G.M., and Heitman, J. 2002. Pheromones stimulate mating and differentiation via paracrine and autocrine signaling in Cryptococcus neoformans. Eukaryot. Cell 1, 366–377.PubMedCentral CrossRef PubMed
  Shen, M., Pan, P., Li, Y., Li, D., Yu, H., and Hou, T. 2015b. Farnesyltransferase and geranylgeranyltransferase I: structures, mechanism, inhibitors and molecular modeling. Drug Discov. Today 20, 267–276.CrossRef PubMed
  Siafakas, A.R., Sorrell, T.C., Wright, L.C., Wilson, C., Larsen, M., Boadle, R., Williamson, P.R., and Djordjevic, J.T. 2007. Cell walllinked cryptococcal phospholipase B1 is a source of secreted enzyme and a determinant of cell wall integrity. J. Biol. Chem. 282, 37508–37514.CrossRef PubMed
  Siafakas, A.R., Wright, L.C., Sorrell, T.C., and Djordjevic, J.T. 2006. Lipid rafts in Cryptococcus neoformans concentrate the virulence determinants phospholipase B1 and Cu/Zn superoxide dismutase. Eukaryot. Cell 5, 488–498.PubMedCentral CrossRef PubMed
  Srikanta, D., Santiago-Tirado, F.H., and Doering, T.L. 2014. Cryptococcus neoformans: historical curiosity to modern pathogen. Yeast 31, 47–60.PubMedCentral CrossRef PubMed
  Umemura, M., Okamoto, M., Nakayama, K., Sagane, K., Tsukahara, K., Hata, K., and Jigami, Y. 2003. GWT1 gene is required for inositol acylation of glycosylphosphatidylinositol anchors in yeast. J. Biol. Chem. 278, 23639–23647.CrossRef PubMed
  Vallim, M.A., Fernandes, L., and Alspaugh, J.A. 2004. The RAM1 gene encoding a protein-farnesyltransferase beta-subunit homologue is essential in Cryptococcus neoformans. Microbiology 150, 1925–1935.CrossRef PubMed
  Watanabe, N.A., Miyazaki, M., Horii, T., Sagane, K., Tsukahara, K., and Hata, K. 2012. E1210, a new broad-spectrum antifungal, suppresses Candida albicans hyphal growth through inhibition of glycosylphosphatidylinositol biosynthesis. Antimicrob. Agents Chemother. 56, 960–971.PubMedCentral CrossRef PubMed
  Young, E., Zheng, Z.Y., Wilkins, A.D., Jeong, H.T., Li, M., Lichtarge, O., and Chang, E.C. 2014. Regulation of Ras localization and cell transformation by evolutionarily conserved palmitoyltransferases. Mol. Cell. Biol. 34, 374–385.PubMedCentral CrossRef PubMed
  Zhang, M.M., Wu, P.Y., Kelly, F.D., Nurse, P., and Hang, H.C. 2013. Quantitative control of protein S-palmitoylation regulates meiotic entry in fission yeast. PLoS Biol. 11, e1001597.PubMedCentral CrossRef PubMed
  
• 作者单位：Felipe H. Santiago-Tirado (1)
  Tamara L. Doering (1)
  
  1. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, 63110, USA
  
• 刊物主题：Microbiology;
• 出版者：Springer Netherlands
• ISSN：1976-3794

文摘

Lipid modification of proteins is a widespread, essential process whereby fatty acids, cholesterol, isoprenoids, phospholipids, or glycosylphospholipids are attached to polypeptides. These hydrophobic groups may affect protein structure, function, localization, and/or stability; as a consequence such modifications play critical regulatory roles in cellular systems. Recent advances in chemical biology and proteomics have allowed the profiling of modified proteins, enabling dissection of the functional consequences of lipid addition. The enzymes that mediate lipid modification are specific for both the lipid and protein substrates, and are conserved from fungi to humans. In this article we review these enzymes, their substrates, and the processes involved in eukaryotic lipid modification of proteins. We further focus on its occurrence in the fungal pathogen Cryptococcus neoformans, highlighting unique features that are both relevant for the biology of the organism and potentially important in the search for new therapies.