Palmitoylation: Policing protein stability and traffic

Nature Reviews Molecular Cell Biology

Volumn 8, Issue 1, 2007, Pages 74-84

  Linder, Maurine E ^a   Deschenes, Robert J ^b  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b MEDICAL COLLEGE OF WISCONSIN   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTHRAX TOXIN; HUNTINGTIN; LIPID; MEMBRANE PROTEIN; PALMITIC ACID; PALMITOYLPROTEOME; PROTEIN; SNARE PROTEIN; UNCLASSIFIED DRUG;

CELL TRANSPORT; HUMAN; NONHUMAN; ONCOGENE RAS; PALMITOYLATION; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN INTERACTION; PROTEIN MODIFICATION; PROTEIN STABILITY; PROTEIN TRANSPORT; REGULATORY MECHANISM; REVIEW; SACCHAROMYCES CEREVISIAE;

ACYLATION; ANIMALS; HUMANS; PALMITIC ACID; PROTEIN TRANSPORT; PROTEINS; PROTEOME; THERMODYNAMICS;

EID: 33845794047     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm2084     Document Type: Review

References (91)

1. Smotrys, J. E. & Linder, M. E. Palmitoylation of intracellular signaling proteins: regulation and function. Annu. Rev. Biochem. 73, 559-587 (2004).
2. Mitchell, D. A., Vasudevan, A., Linder, M. E. & Deschenes, R. J. Protein pamitoylation by a family of DHHC protein S-acyltransferases. J. Lipid Res. 47, 11188-11127 (2006).
3. Pepinsky, R. B. et al. Identification of a palmitic acid-modified form of human Sonic hedgehog. J. Biol. Chem. 273, 14037-14045 (1998).
4. Resh, M. Fatty acylation of proteins: new insights into membrane targeting of myristoylated and palmitoylated proteins. Biochim. Biophys. Acta 1451, 1-16 (1999).
5. Zhang, F. L. & Casey, P. J. Protein prenylation: molecular mechanisms and functional consequences. Annu. Rev. Biochem. 65, 241-270 (1996).
6. Schafer, W. R. & Rine, J. Protein prenylation: genes, enzymes, targets, and functions. Annu. Rev. Genetics 30, 209-237 (1992).
7. Mann, R. K. & Beachy, P. A. Novel lipid modifications of secreted protein signals. Annu. Rev. Biochem. 73, 891-923 (2004).
8. Miura, G. I. & Treisman, J. E. Lipid modification of secreted signaling proteins. Cell Cycle 5, 1184-1188 (2006).
9. Schmidt, M. F. G. & Schlesinger, M. J. Relation of fatty acid attachment to the translation and mautration of vesicular stomatitis and Sindbis virus membrane glycoproteins. J. Biol. Chem. 255, 3334-3339 (1980).
10. Veit, M. & Schmidt, M. F. Timing of palmitoylation of influenza virus hemagglutinin. FEBS Lett. 336, 243-247 (1993).
11. Mumby, S. M., Kleuss, C. & Gilman, A. G. Receptor regulation of G protein palmitoylation. Proc. Natl Acad. Sci. USA 91, 2800-2804 (1994).
12. 3H]palmitic acid and mutation of cysteine-3 prevents this modification. Biochemistry 32, 8057-8061 (1993).
13. sα. Cell 77, 1063-1070 (1994).
14. Lu, J. Y. & Hofmann, S. L. Lysosomal metabolism of lipid-modified proteins. J. Lipid Res. 47, 1352-1357 (2006).
15. Magee, T. & Seabra, M. C. Fatty acylation and prenylation of proteins: what's hot in fat. Curr. Opin. Cell Biol. 17, 190-196 (2005).
16. Bano, M. C., Jackson, C. S. & Magee, A. I. Pseudoenzymatic S-acylation of a myristoylated Yes protein tyrosine kinase peptide in vitro may reflect nonenzymatic S-acylation in vivo. Biochem. J. 330, 723-731 (1998).
17. Lobo, S., Greentree, W., Linder, M. & Deschenes, R. Identification of a Ras palmitoyltransferase in Saccharomyces cerevisiae. J. Biol. Chem. 277, 41268-41273 (2002).
18. Roth, A., Feng, Y., Chen, L. & Davis, N. The yeast DHHC cysteine-rich domain protein Akr1p is a palmitoyl transferase. J. Cell Biol. 159, 23-28 (2002). References 17 and 18 are the first to show that proteins with DHHC domains are PATs.
19. Fukata, M., Fukata, Y., Adesnik, H., Nicoll, R. A. & Bredt, D. S. Identification of PSD-95 palmitoylating enzymes. Neuron 44, 987-996 (2004). Cloning and expression of the 23 members of the murine family of DHHC proteins, identifying a subset that are PATs for the neuronal scaffold protein PSD95.
20. Ducker, C. E., Stettler, E. M., French, K. J., Upson, J. J. & Smith, C. D. Huntingtin interacting protein 14 is an oncogenic human protein: palmitoyl acyltransferase. Oncogene 23, 9230-9237 (2004).
21. Huang, K. et al. Huntingtin-interacting protein HIP14 is a palmitoyl transferase involved in palmitoylation and trafficking of multiple neuronal proteins. Neuron 44, 977-986 (2004).
22. Keller, C. A. et al. The γ2 subunit of GABA(A) receptors is a substrate for palmitoylation by GODZ. J. Neurosci. 24, 5881-5891 (2004).
23. Swarthout, J. T. et al. DHHC9 and GCP16 constitute a human protein fatty acyltransferase with specificity for H- and N-Ras. J. Biol. Chem. 280, 31141-31148 (2005).
24. Hayashi, T., Rumbaugh, G. & Huganir, R. L. Differential regulation of AMPA receptor subunit trafficking by palmitoylation of two distinct sites. Neuron 47, 709-723 (2005).
25. Fernandez-Hernando, C. et al. Identification of Golgi-localized acyl transferases that palmitoylate and regulate endothelial nitric oxide synthase. J. Cell Biol. 174, 369-377 (2006).
26. Hundt, M. et al. Impaired activation and localization of LAT in anergic T cells as a consequence of a selective palmitoylation defect. Immunity 24, 513-522 (2006).
27. Ohno, Y., Kihara, A., Sano, T. & Igarashi, Y. Intracellular localization and tissue-specific distribution of human and yeast DHHC cysteine-rich domain-containing proteins. Biochim. Biophys. Acta 1761, 474-483 (2006). A comprehensive survey of the localization and tissue distribution of yeast and human DHHC proteins.
28. Sugimoto, H., Hayashi, H. & Yamashita, S. Purification, cDNA cloning, and regulation of lysophospholipase from rat liver. J. Biol. Chem. 271, 7705-7711 (1996).
29. Duncan, J. A. & Gilman, A. G. A cytoplasmic acylprotein thioesterase that removes palmitate from G protein á subunits and p21Ras. J. Biol. Chem. 273, 15830-15837 (1998).
30. 2+-calmodulin. J. Biol. Chem. 274, 33148-33154 (1999).
31. Duncan, J. & Gilman, A. Characterization of Saccharomyces cerevisiae acyl-protein thioesterase 1, the enzyme responsible for G protein α subunit deacylation in vivo. J. Biol. Chem. 277, 31740-31752 (2002).
32. Verkruyse, L. & Hofmann, S. Lysosomal targeting of palmitoyl-protein thioesterase. J. Biol. Chem. 271, 15831-15836 (1996).
33. Vesa, J. et al. Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature 376, 584-587 (1995).
34. Gupta, P. et al. Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. Proc. Natl Acad. Sci. USA 98, 13566-13571 (2001).
35. Schmidt, M. F. G. & Schlesinger, M. J. Fatty acid binding to vesicular stomatitis virus glycoprotein - a new type of posttranslational modification of the viral glycoprotein. Cell 17, 813-819 (1979).
36. Roth, A. F. et al. Global analysis of protein palmitoylation in yeast. Cell 125, 1003-1013 (2006). The first systematic analysis of a palmitoylproteome using acylbiotin-exchange chemistry and mass spectroscopy.
37. Valdez-Taubas, J. & Pelham, H. Swf1-dependent palmitoylation of the SNARE Tlg1 prevents its ubiquitination and degradation. EMBO J. 24, 2524-2532 (2005). First study to link DHHC PATs with the palmitoylation of integral membrane proteins and to identify a reciprocal relationship between palmitoylation and ubiquitylation.
38. Bartels, D. J., Mitchell, D. A., Dong, X. & Deschenes, R. J. Erf2, a novel gene product that affects the localization and palmitoylation of Ras2 in Saccharomyces cerevisiae. Mol. Cell. Biol. 19, 6775-6787 (1999).
39. Smotrys, J. E., Schoenfish, M. J., Stutz, M. A. & Linder, M. E. The vacuolar DHHC-CRD protein Pfa3p is a protein acyltransferase for Vac8p. J. Cell Biol. 170, 1091-1099 (2005).
40. Xue, L., Gollapalli, D. R., Maiti, P., Jahng, W. J. & Rando, R. R. A palmitoylation switch mechanism in the regulation of the visual cycle. Cell 117, 761-771 (2004).
41. Corvi, M., Soltys, C.-L. M. & Berthiaume, L. Regulation of mitochondrial carbamoyl-phosphate synthetase I activity by active site fatty acylation. J. Biol. Chem. 276, 45704-45712 (2001).
42. Kummel, D., Heinemann, U. & Veit, M. Unique self-palmitoylation activity of the transport protein particle component Bet3: a mechanism required for protein stability. Proc. Natl Acad. Sci. USA 103, 12701-12706 (2006).
43. Plowman, S. J. & Hancock, J. F. Ras signaling from plasma membrane and endomembrane microdomains. Biochim. Biophys. Acta 1746, 274-283 (2005).
44. Mor, A. & Philips, M. R. Compartmentalized Ras/MAPK signaling. Annu. Rev. Immunol. 24, 771-800 (2006).
45. Wright, L. P. & Philips, M. R. Thematic review series: lipid posttranslational modifications. CAAX modification and membrane targeting of Ras. J. Lipid Res. 47, 883-891 (2006).
46. El-Husseini, A.-D. & Bredt, D. S. Protein palmitoylation: a regulator of neuronal development and function. Nature Rev. Neurosci. 3, 791-802 (2002).
47. Huang, K. & El-Husseini, A.-D. Modulation of neuronal protein trafficking and function by palmitoylation. Curr. Opin. Neurobiol. 15, 527-535 (2005).
48. Michaelson, D. et al. Postprenylation CAAX processing is required for proper localization of Ras but not Rho GTPases. Mol. Biol. Cell 16, 1606-1616 (2005).
49. Roy, S. et al. Individual palmitoyl residues serve distinct roles in H-ras trafficking, microlocalization, and signaling. Mol. Cell. Biol. 25, 6722-6733 (2005). Shows that the two palmitoylated residues on the H-Ras protein are functionally distinct.
50. Magee, A. I., Gutierrez, L., McKay, I. A., Marshall, C. J. & Hall, A. Dynamic fatty acylation of p21N-ras. EMBO J. 6, 3353-3357 (1987).
51. Lu, J. Y. & Hofmann, S. L. Depalmitoylation of CAAX motif proteins. Protein structural determinants of palmitate turnover rate. J. Biol. Chem. 270, 7251-7256 (1995).
52. Baker, T. L., Zheng, H., Walker, J., Coloff, J. L. & Buss, J. E. Distinct rates of palmitate turnover on membrane-bound cellular and oncogenic H-ras. J. Biol. Chem. 278, 19292-19300 (2003).
53. Rocks, O. et al. An acylation cycle regulates localization and activity of palmitoylated Ras isoforms. Science 307, 1746-1752 (2005). Shows that Ras proteins shuttle between the Golgi and plasma membrane in a palmitoylation- dependent manner.
54. Goodwin, J. S. et al. Depalmitoylated Ras traffics to and from the Golgi complex via a nonvesicular pathway. J. Cell Biol. 170, 261-272 (2005). Shows that Ras proteins rapidly exchange between the cytosol and membranes unless they are palmitoylated.
55. Choy, E. et al. Endomembrane trafficking of Ras: the CAAX motif targets proteins to the ER and Golgi. Cell 98, 69-80 (1999).
56. Appolloni, A., Prior, I., Lindsay, M., Parton, R. & Hancock, J. H-ras but not K-ras traffics to the plasma membrane through the exocytic pathway. Mol. Cell. Biol. 20, 2475-2487 (2000).
57. Shahinian, S. & Silvius, J. R. Doubly-lipid-modified protein sequence motifs exhibit long-lived anchorage to lipid bilayer membranes. Biochemistry 34, 3813-3822 (1995).
58. Zhao, L., Lobo, S., Dong, X., Ault, A. D. & Deschenes, R. J. Erf4p and Erf2p form an endoplasmic reticulum-associated complex involved in the plasma membrane localization of yeast Ras proteins. J. Biol. Chem. 277, 49352-49359 (2002).
59. Dong, X. et al. Palmitoylation and plasma membrane localization of Ras2p by a nonclassical trafficking pathway in Saccharomyces cerevisiae. Mol. Cell. Biol. 23, 6574-6584 (2003).
60. Wang, G. & Deschenes, R. J. Plasma membrane localization of Ras requires class C Vps proteins and functional mitochondria in Saccharomyces cerevisiae. Mol. Cell. Biol. 26, 3243-3255 (2006).
61. Gao, Z., Ni, Y., Szabo, G. & Linden, J. Palmitoylation of the recombinant human A1 adenosine receptor: enhanced proteolysis of palmitoylation-deficient mutant receptors. Biochem. J. 342, 387-395 (1999).
62. Percherancier, Y. et al. Palmitoylation-dependent control of degradation, life span, and membrane expression of the CCR5 receptor. J. Biol. Chem. 276, 31936-31944 (2001).
63. Ochsenbauer-Jambor, C., Miller, D. C., Roberts, C. R., Rhee, S. S. & Hunter, E. Palmitoylation of the Rous sarcoma virus transmembrane glycoprotein is required for protein stability and virus infectivity. J. Virol. 75, 11544-11554 (2001).
64. Abrami, L., Leppla, S. H. & van der Goot, F. G. Receptor palmitoylation and ubiquitination regulate anthrax toxin endocytosis. J. Cell Biol. 172, 309-320 (2006). Shows a role for palmitoylation as a mechanism to protect a protein from degradation by inhibiting trafficking to a compartment where the protein is ubiquitylated.
65. Hershko, A., Ciechanover, A. & Varshavsky, A. Basic medical research award. The ubiquitin system. Nature Med. 6, 1073-1081 (2000).
66. Hicke, L. & Dunn, R. Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Annu. Rev. Cell Dev. Biol. 19, 141-172 (2003).
67. Siniossoglou, S. & Pelham, H. R. An effector of Ypt6p binds the SNARE Tlg1p and mediates selective fusion of vesicles with late Golgi membranes. EMBO J. 20, 5991-5998 (2001).
68. Coe, J. G., Lim, A. C., Xu, J. & Hong, W. A role for Tlg1p in the transport of proteins within the Golgi apparatus of Saccharomyces cerevisiae. Mol. Biol. Cell 10, 2407-2423 (1999).
69. Reggiori, F. & Pelham, H. R. A transmembrane ubiquitin ligase required to sort membrane proteins into multivesicular bodies. Nature Cell Biol. 4, 117-123 (2002).
70. Hettema, E. H., Valdez-Taubas, J. & Pelham, H. R. Bsd2 binds the ubiquitin ligase Rsp5 and mediates the ubiquitination of transmembrane proteins. EMBO J. 23, 1279-1288 (2004).
71. Abrami, L., Reig, N. & van der Goot, F. G. Anthrax toxin: the long and winding road that leads to the kill. Trends Microbiol. 13, 72-78 (2005).
72. Bann, J. G., Cegelski, L. & Hultgren, S. J. LRP6 holds the key to the entry of anthrax toxin. Cell 124, 1119-1121 (2006).
73. Scobie, H. M. & Young, J. A. Interactions between anthrax toxin receptors and protective antigen. Curr. Opin. Microbiol. 8, 106-112 (2005).
74. Wei, W., Lu, Q., Chaudry, G. J., Leppla, S. H. & Cohen, S. N. The LDL receptor-related protein LRP6 mediates internalization and lethality of anthrax toxin. Cell 124, 1141-1154 (2006).
75. Abrami, L., Liu, S., Cosson, P., Leppla, S. H. & van der Goot, F. G. Anthrax toxin triggers endocytosis of its receptor via a lipid raft-mediated clathrin-dependent process. J. Cell Biol. 160, 321-328 (2003).
76. Dietzen, D. J., Hastings, W. R. & Lublin, D. M. Caveolin is palmitoylated on multiple cysteine residues. Palmitoylation is not necessary for localization of caveolin to caveolae. J. Biol. Chem. 270, 6838-6342 (1995).
77. Alvarez, E., Girones, N. & Davis, R. J. Inhibition of the receptor-mediated endocytosis of diferric transferrin is associated with the covalent modification of the transferrin receptor with palmitic acid. J. Biol. Chem. 265, 16644-16655 (1990).
78. Mack, D. & Kruppa, J. Fatty acid acylation at the single cysteine residue in the cytoplasmic domain of the glycoprotein of vesicular-stomatitis virus. Biochem. J. 256, 1021-1027 (1988).
79. Yanai, A. et al. Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function. Nature Neurosci. 9, 824-831 (2006). Shows that huntingtin is palmitoylated and that palmitoylation inhibits aggregation of mutant forms of huntingtin.
80. Landles, C. & Bates, G. P. Huntingtin and the molecular pathogenesis of Huntington's disease. Fourth in molecular medicine review series. EMBO Rep. 5, 958-963 (2004).
81. Kalchman, M. A. et al. Huntingtin is ubiquitinated and interacts with a specific ubiquitin-conjugating enzyme. J. Biol. Chem. 271, 19385-19394 (1996).
82. Steffan, J. S. et al. SUMO modification of huntingtin and Huntington's disease pathology. Science 304, 100-104 (2004).
83. Ducker, C. E. et al. Discovery and characterization of inhibitors of human palmitoyl acyltransferases. Mol. Cancer Ther. 5, 1647-1659 (2006).
84. Biel, M., Deck, P., Giannis, A. & Waldmann, H. Synthesis and evaluation of acyl protein thioesterase 1 (APT1) inhibitors. Chemistry 12, 4121-4143 (2006).
85. Drisdel, R. C. & Green, W. N. Labeling and quantifying sites of protein palmitoylation. Biotechniques 36, 276-285 (2004).
86. Politis, E. G., Roth, A. F. & Davis, N. G. Transmembrane topology of the protein palmitoyl transferase Akr1. J. Biol. Chem. 280, 10156-10163 (2005).
87. Hou, H. et al. The DHHC protein Pfa3 affects vacuole-associated palmitoylation of the fusion factor Vac8. Proc. Natl Acad. Sci. USA 102, 17366-17371 (2005).
88. Singaraja, R. R. et al. HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis. Hum. Mol. Genet. 11, 2815-2828 (2002).
89. Kihara, A., Kurotsu, F., Sano, T., Iwaki, S. & Igarashi, Y. Long-chain base kinase Lcb4 is anchored to the membrane through its palmitoylation by Akr1. Mol. Cell. Biol. 25, 9189-9197 (2005).
90. Babu, P., Deschenes, R. J. & Robinson, L. C. Akr1p-dependent palmitoylation of Yck2p yeast casein kinase 1 is necessary and sufficient for plasma membrane targeting. J. Biol. Chem. 279, 27138-27147 (2004).
91. Lam, K. K. et al. Palmitoylation by the DHHC protein Pfa4 regulates the ER exit of Chs3. J. Cell Biol. 174, 19-25 (2006).