The HERV-K human endogenous retrovirus envelope protein antagonizes tetherin antiviral activity

Journal of Virology

Volumn 88, Issue 23, 2014, Pages 13626-13637

  Lemaître, Cécile ^a,b,c   Harper, Francis ^a,b   Pierron, Gérard ^a,b   Heidmann, Thierry ^a,b   Dewannieux, Marie ^a,b  

^a INSTITUT GUSTAVE ROUSSY   (France)

^b UNIVERSITÉ PARIS SACLAY   (France)

^c UNIVERSITÉ PARIS DESCARTES   (France)

Author keywords

[No Author keywords available]

Indexed keywords

CELL PROTEIN; EBOLA GLYCOPROTEIN; HERV K VIRUS ENVELOPE PROTEIN; TETHERIN; UNCLASSIFIED DRUG; VIRUS ENVELOPE PROTEIN; VIRUS GLYCOPROTEIN; BST2 PROTEIN, HUMAN; GLYCOSYLPHOSPHATIDYLINOSITOL ANCHORED PROTEIN; LEUKOCYTE ANTIGEN;

ALLELE; ANTIVIRAL ACTIVITY; ARTICLE; CELL SURFACE; CONTROLLED STUDY; ENDOGENOUS RETROVIRUS; HERV K ENDOGENOUS RETROVIRUS; IMMUNOPRECIPITATION; INHIBITION KINETICS; INNATE IMMUNITY; NONHUMAN; PHARMACOLOGICAL BLOCKING; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN RESTRICTION; PROTEIN SUBUNIT; RETROVIRUS INFECTION; VIRUS INHIBITION; VIRUS PARTICLE; VIRUS RELEASE; ANTAGONISTS AND INHIBITORS; CELL LINE; HUMAN; IMMUNOLOGY; METABOLISM;

HUMAN ENDOGENOUS RETROVIRUS;

ANTIGENS, CD; CELL LINE; ENDOGENOUS RETROVIRUSES; GPI-LINKED PROTEINS; HUMANS; IMMUNOPRECIPITATION; VIRAL ENVELOPE PROTEINS;

EID: 84909990525     PISSN: 0022538X     EISSN: 10985514     Source Type: Journal    
DOI: 10.1128/JVI.02234-14     Document Type: Article

References (72)

1. Bannert N, Kurth R. 2004. Retroelements and the human genome: new perspectives on an old relation. Proc. Natl. Acad. Sci. U. S. A. 101(Suppl 2):S14572-S14579. http://dx.doi.org/10.1073/pnas.0404838101.
2. Stoye JP. 2012. Studies of endogenous retroviruses reveal a continuing evolutionary saga. Nat. Rev. Microbiol. 10:395-406. http://dx.doi.org/10.1038/nrmicro2783.
3. Feschotte C, Gilbert C. 2012. Endogenous viruses: insights into viral evolution and impact on host biology. Nat. Rev. Genet. 13:283-296. http://dx.doi.org/10.1038/nrg3199.
4. Dewannieux M, Heidmann T. 2013. Endogenous retroviruses: acquisition, amplification and taming of genome invaders. Curr. Opin. Virol. 3:646-656. http://dx.doi.org/10.1016/j.coviro.2013.08.005.
5. Blond JL, Lavillette D, Cheynet V, Bouton O, Oriol G, Chapel-Fernandes S, Mandrand B, Mallet F, Cosset FL. 2000. An envelope glycoprotein of the human endogenous retrovirus HERV-W is expressed in the human placenta and fuses cells expressing the type D mammalian retrovirus receptor. J. Virol. 74:3321-3329. http://dx.doi.org/10.1128/JVI.74.7.3321-3329.2000.
6. Mi S, Lee X, Li X, Veldman GM, Finnerty H, Racie L, LaVallie E, Tang XY, Edouard P, Howes S, Keith JC, Jr, McCoy JM. 2000. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403:785-789. http://dx.doi.org/10.1038/35001608.
7. Blaise S, de Parseval N, Benit L, Heidmann T. 2003. Genomewide screening for fusogenic human endogenous retrovirus envelopes identifies syncytin 2, a gene conserved on primate evolution. Proc. Natl. Acad. Sci. U. S. A. 100:13013-13018. http://dx.doi.org/10.1073/pnas.2132 646100.
8. Medstrand P, Mager DL. 1998. Human-specific integrations of the HERV-K endogenous retrovirus family. J. Virol. 72:9782-9787.
9. Subramanian RP, Wildschutte JH, Russo C, Coffin JM. 2011. Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology 8:90. http://dx.doi.org/10.1186/1742-4690-8-90.
10. Magiorkinis G, Belshaw R, Katzourakis A. 2013. "There and back again": revisiting the pathophysiological roles of human endogenous retroviruses in the post-genomic era. Philos. Trans. R. Soc. Lond. B Biol. Sci. 368: 20120504. http://dx.doi.org/10.1098/rstb.2012.0504.
11. Turner G, Barbulescu M, Su M, Jensen-Seaman MI, Kidd KK, Lenz J. 2001. Insertional polymorphisms of full-length endogenous retroviruses in humans. Curr. Biol. 11:1531-1535. http://dx.doi.org/10.1016/S0960 -9822(01)00455-9.
12. Belshaw R, Dawson AL, Woolven-Allen J, Redding J, Burt A, Tristem M. 2005. Genomewide screening reveals high levels of insertional polymorphism in the human endogenous retrovirus family HERV-K(HML2): implications for present-day activity. J. Virol. 79:12507-12514. http://dx.doi.org/10.1128/JVI.79.19.12507-12514.2005.
13. Lower R, Tonjes RR, Korbmacher C, Kurth R, Lower J. 1995. Identification of a Rev-related protein by analysis of spliced transcripts of the human endogenous retroviruses HTDV/HERV-K. J. Virol. 69:141-149.
14. Yang J, Bogerd HP, Peng S, Wiegand H, Truant R, Cullen BR. 1999. An ancient family of human endogenous retroviruses encodes a functional homolog of the HIV-1 Rev protein. Proc. Natl. Acad. Sci. U. S. A. 96: 13404-13408. http://dx.doi.org/10.1073/pnas.96.23.13404.
15. Boller K, Konig H, Sauter M, Mueller-Lantzsch N, Lower R, Lower J, Kurth R. 1993. Evidence that HERV-K is the endogenous retrovirus sequence that codes for the human teratocarcinoma-derived retrovirus HTDV. Virology 196:349-353. http://dx.doi.org/10.1006/viro.1993.1487.
16. Bieda K, Hoffmann A, Boller K. 2001. Phenotypic heterogeneity of human endogenous retrovirus particles produced by teratocarcinoma cell lines. J. Gen. Virol. 82:591-596.
17. Muster T, Waltenberger A, Grassauer A, Hirschl S, Caucig P, Romirer I, Fodinger D, Seppele H, Schanab O, Magin-Lachmann C, Lower R, Jansen B, Pehamberger H, Wolff K. 2003. An endogenous retrovirus derived from human melanoma cells. Cancer Res. 63:8735-8741.
18. Buscher K, Trefzer U, Hofmann M, Sterry W, Kurth R, Denner J. 2005. Expression of human endogenous retrovirus K in melanomas and melanoma cell lines. Cancer Res. 65:4172-4180. http://dx.doi.org/10.1158/0008-5472.CAN-04-2983.
19. Dewannieux M, Blaise S, Heidmann T. 2005. Identification of a functional envelope protein from the HERV-K family of human endogenous retroviruses. J. Virol. 79:15573-15577. http://dx.doi.org/10.1128/JVI.79.24.15573-15577.2005.
20. Neil SJ, Zang T, Bieniasz PD. 2008. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 451:425-430. http://dx.doi.org/10.1038/nature06553.
21. Van Damme N, Goff D, Katsura C, Jorgenson RL, Mitchell R, Johnson MC, Stephens EB, Guatelli J. 2008. The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein. Cell Host Microbe 3:245-252. http://dx.doi.org/10.1016/j.chom.2008.03.001.
22. Jouvenet N, Neil SJ, Zhadina M, Zang T, Kratovac Z, Lee Y, McNatt M, Hatziioannou T, Bieniasz PD. 2009. Broad-spectrum inhibition of ret-roviral and filoviral particle release by tetherin. J. Virol. 83:1837-1844. http://dx.doi.org/10.1128/JVI.02211-08.
23. Neil SJ. 2013. The antiviral activities of tetherin. Curr. Top. Microbiol. Immunol. 371:67-104. http://dx.doi.org/10.1007/978-3-642-37765-5_3.
24. Rollason R, Korolchuk V, Hamilton C, Schu P, Banting G. 2007. Clathrin-mediated endocytosis of a lipid-raft-associated protein is mediated through a dual tyrosine motif. J. Cell Sci. 120:3850-3858. http://dx.doi.org/10.1242/jcs.003343.
25. Kupzig S, Korolchuk V, Rollason R, Sugden A, Wilde A, Banting G. 2003. Bst-2/HM1.24 is a raft-associated apical membrane protein with an unusual topology. Traffic 4:694-709. http://dx.doi.org/10.1034/j.1600 -0854.2003.00129.x.
26. Andrew AJ, Miyagi E, Kao S, Strebel K. 2009. The formation of cysteinelinked dimers of BST-2/tetherin is important for inhibition of HIV-1 virus release but not for sensitivity to Vpu. Retrovirology 6:80. http://dx.doi.org/10.1186/1742-4690-6-80.
27. Perez-Caballero D, Zang T, Ebrahimi A, McNatt MW, Gregory DA, Johnson MC, Bieniasz PD. 2009. Tetherin inhibits HIV-1 release by directly tethering virions to cells. Cell 139:499-511. http://dx.doi.org/10.1016/j.cell.2009.08.039.
28. Neil SJ, Sandrin V, Sundquist WI, Bieniasz PD. 2007. An interferonalpha-induced tethering mechanism inhibits HIV-1 and Ebola virus particle release but is counteracted by the HIV-1 Vpu protein. Cell Host Microbe 2:193-203. http://dx.doi.org/10.1016/j.chom.2007.08.001.
29. Liberatore RA, Bieniasz PD. 2011. Tetherin is a key effector of the antiretroviral activity of type I interferon in vitro and in vivo. Proc. Natl. Acad.Sci.U.S.A.108:18097-18101.http://dx.doi.org/10.1073/pnas.11136 94108.
30. Galao RP, Le Tortorec A, Pickering S, Kueck T, Neil SJ. 2012. Innate sensing of HIV-1 assembly by Tetherin induces NFkappaB-dependent proinflammatory responses. Cell Host Microbe 12:633-644. http://dx.doi.org/10.1016/j.chom.2012.10.007.
31. Tokarev A, Suarez M, Kwan W, Fitzpatrick K, Singh R, Guatelli J. 2013. Stimulation of NF-kappaB activity by the HIV restriction factor BST2. J. Virol. 87:2046-2057. http://dx.doi.org/10.1128/JVI.02272-12.
32. Lim ES, Emerman M. 2009. Simian immunodeficiency virus SIVagm from African green monkeys does not antagonize endogenous levels of African green monkey tetherin/BST-2. J. Virol. 83:11673-11681. http://dx.doi.org/10.1128/JVI.00569-09.
33. Yang SJ, Lopez LA, Hauser H, Exline CM, Haworth KG, Cannon PM. 2010. Anti-tetherin activities in Vpu-expressing primate lentiviruses. Retrovirology 7:13. http://dx.doi.org/10.1186/1742-4690-7-13.
34. Zhang F, Wilson SJ, Landford WC, Virgen B, Gregory D, Johnson MC, Munch J, Kirchhoff F, Bieniasz PD, Hatziioannou T. 2009. Nef proteins from simian immunodeficiency viruses are tetherin antagonists. Cell Host Microbe 6:54-67. http://dx.doi.org/10.1016/j.chom.2009.05.008.
35. Jia B, Serra-Moreno R, Neidermyer W, Rahmberg A, Mackey J, Fofana IB, Johnson WE, Westmoreland S, Evans DT. 2009. Species-specific activity of SIV Nef and HIV-1 Vpu in overcoming restriction by tetherin/BST2. PLoS Pathog. 5:e1000429. http://dx.doi.org/10.1371/journal.ppat.1000429.
36. Sauter D, Schindler M, Specht A, Landford WN, Munch J, Kim KA, Votteler J, Schubert U, Bibollet-Ruche F, Keele BF, Takehisa J, Ogando Y, Ochsenbauer C, Kappes JC, Ayouba A, Peeters M, Learn GH, Shaw G, Sharp PM, Bieniasz P, Hahn BH, Hatziioannou T, Kirchhoff F. 2009. Tetherin-driven adaptation of Vpu and Nef function and the evolution of pandemic and nonpandemic HIV-1 strains. Cell Host Microbe 6:409- 421. http://dx.doi.org/10.1016/j.chom.2009.10.004.
37. Bartee E, McCormack A, Fruh K. 2006. Quantitative membrane proteomics reveals new cellular targets of viral immune modulators. PLoS Pathog. 2:e107. http://dx.doi.org/10.1371/journal.ppat.0020107.
38. Mansouri M, Viswanathan K, Douglas JL, Hines J, Gustin J, Moses AV, Fruh K. 2009. Molecular mechanism of BST2/tetherin downregulation by K5/MIR2 of Kaposi's sarcoma-associated herpesvirus. J. Virol. 83:9672- 9681. http://dx.doi.org/10.1128/JVI.00597-09.
39. Pardieu C, Vigan R, Wilson SJ, Calvi A, Zang T, Bieniasz P, Kellam P, Towers GJ, Neil SJ. 2010. The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin. PLoS Pathog. 6:e1000843. http://dx.doi.org/10.1371/journal.ppat.1000843.
40. Le Tortorec A, Neil SJ. 2009. Antagonism to and intracellular sequestration of human tetherin by the human immunodeficiency virus type 2 envelope glycoprotein. J. Virol. 83:11966-11978. http://dx.doi.org/10.1128/JVI.01515-09.
41. Gupta RK, Mlcochova P, Pelchen-Matthews A, Petit SJ, Mattiuzzo G, Pillay D, Takeuchi Y, Marsh M, Towers GJ. 2009. Simian immunodeficiency virus envelope glycoprotein counteracts tetherin/BST-2/CD317 by intracellular sequestration. Proc. Natl. Acad. Sci. U. S. A. 106:20889- 20894. http://dx.doi.org/10.1073/pnas.0907075106.
42. Celestino M, Calistri A, Del Vecchio C, Salata C, Chiuppesi F, Pistello M, Borsetti A, Palu G, Parolin C. 2012. Feline tetherin is characterized by a short N-terminal region and is counteracted by the feline immunodeficiency virus envelope glycoprotein. J. Virol. 86:6688-6700. http://dx.doi.org/10.1128/JVI.07037-11.
43. Dietrich I, McMonagle EL, Petit SJ, Vijayakrishnan S, Logan N, Chan CN, Towers GJ, Hosie MJ, Willett BJ. 2011. Feline tetherin efficiently restricts release of feline immunodeficiency virus but not spreading of infection. J. Virol. 85:5840 -5852. http://dx.doi.org/10.1128/JVI.00071-11.
44. Morrison JH, Guevara RB, Marcano A, Saenz DT, Fadel HJ, Rogstad DK, Poeschla EM. 2014. FIV envelope glycoproteins antagonize Tetherin through a distinctive mechanism that requires virion incorporation. J. Virol. 88:3255-3272. http://dx.doi.org/10.1128/JVI.03814-13.
45. Yin X, Hu Z, Gu Q, Wu X, Zheng YH, Wei P, Wang X. 2014. Equine tetherin blocks retrovirus release and its activity is antagonized by equine infectious anemia virus envelope protein. J. Virol. 88:1259-1270. http://dx.doi.org/10.1128/JVI.03148-13.
46. Kaletsky RL, Francica JR, Agrawal-Gamse C, Bates P. 2009. Tetherinmediated restriction of filovirus budding is antagonized by the Ebola glycoprotein. Proc. Natl. Acad. Sci. U. S. A. 106:2886-2891. http://dx.doi.org/10.1073/pnas.0811014106.
47. Lee YN, Bieniasz PD. 2007. Reconstitution of an infectious human endogenous retrovirus. PLoS Pathog. 3:e10. http://dx.doi.org/10.1371/journal.ppat.0030010.
48. Lopez LA, Yang SJ, Hauser H, Exline CM, Haworth KG, Oldenburg J, Cannon PM. 2010. Ebola virus glycoprotein counteracts BST-2/Tetherin restriction in a sequence-independent manner that does not require tetherin surface removal. J. Virol. 84:7243-7255. http://dx.doi.org/10.1128/JVI.02636-09.
49. Kuhl A, Banning C, Marzi A, Votteler J, Steffen I, Bertram S, Glowacka I, Konrad A, Sturzl M, Guo JT, Schubert U, Feldmann H, Behrens G, Schindler M, Pohlmann S. 2011. The Ebola virus glycoprotein and HIV-1 Vpu employ different strategies to counteract the antiviral factor tetherin. J. Infect. Dis. 204(Suppl 3):S850-S860. http://dx.doi.org/10.1093/infdis/jir378.
50. Zufferey R, Nagy D, Mandel RJ, Naldini L, Trono D. 1997. Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat. Biotechnol. 15:871-875. http://dx.doi.org/10.1038/nbt0997-871.
51. Demaison C, Parsley K, Brouns G, Scherr M, Battmer K, Kinnon C, Grez M, Thrasher AJ. 2002. High-level transduction and gene expression in hematopoietic repopulating cells using a human immunodeficiency [correction of imunodeficiency] virus type 1-based lentiviral vector containing an internal spleen focus forming virus promoter. Hum. Gene Ther. 13:803-813. http://dx.doi.org/10.1089/10430340252898984.
52. McNatt MW, Zang T, Hatziioannou T, Bartlett M, Fofana IB, Johnson WE, Neil SJ, Bieniasz PD. 2009. Species-specific activity of HIV-1 Vpu and positive selection of tetherin transmembrane domain variants. PLoS Pathog. 5:e1000300. http://dx.doi.org/10.1371/journal.ppat.1000300.
53. Sandrin V, Muriaux D, Darlix JL, Cosset FL. 2004. Intracellular trafficking of Gag and Env proteins and their interactions modulate pseudotyping of retroviruses. J. Virol. 78:7153-7164. http://dx.doi.org/10.1128/JVI.78.13.7153-7164.2004.
54. Bour SP, Aberham C, Perrin C, Strebel K. 1999. Lack of effect of cytoplasmic tail truncations on human immunodeficiency virus type 2 ROD env particle release activity. J. Virol. 73:778-782.
55. Vigan R, Neil SJ. 2010. Determinants of tetherin antagonism in the transmembrane domain of the human immunodeficiency virus type 1 Vpu protein. J. Virol. 84:12958-12970. http://dx.doi.org/10.1128/JVI.01699-10.
56. Dewannieux M, Harper F, Richaud A, Letzelter C, Ribet D, Pierron G, Heidmann T. 2006. Identification of an infectious progenitor for the multiple-copy HERV-K human endogenous retroelements. Genome Res. 16:1548-1556. http://dx.doi.org/10.1101/gr.5565706.
57. Lee SW, Kahn ML, Dichek DA. 1992. Expression of an anchored urokinase in the apical endothelial cell membrane. Preservation of enzymatic activity and enhancement of cell surface plasminogen activation. J. Biol. Chem. 267:13020-13027.
58. Ragheb JA, Anderson WF. 1994. Uncoupled expression of Moloney murine leukemia virus envelope polypeptides SU and TM: a functional analysis of the role of TM domains in viral entry. J. Virol. 68:3207-3219.
59. Dube M, Roy BB, Guiot-Guillain P, Binette J, Mercier J, Chiasson A, Cohen EA. 2010. Antagonism of tetherin restriction of HIV-1 release by Vpu involves binding and sequestration of the restriction factor in a perinuclear compartment. PLoS Pathog. 6:e1000856. http://dx.doi.org/10.1371/journal.ppat.1000856.
60. Mangeat B, Gers-Huber G, Lehmann M, Zufferey M, Luban J, Piguet V. 2009. HIV-1 Vpu neutralizes the antiviral factor Tetherin/BST-2 by binding it and directing its beta-TrCP2-dependent degradation. PLoS Pathog. 5:e1000574. http://dx.doi.org/10.1371/journal.ppat.1000574.
61. Iwabu Y, Fujita H, Kinomoto M, Kaneko K, Ishizaka Y, Tanaka Y, Sata T, Tokunaga K. 2009. HIV-1 accessory protein Vpu internalizes cellsurface BST-2/tetherin through transmembrane interactions leading to lysosomes. J. Biol. Chem. 284:35060-35072. http://dx.doi.org/10.1074/jbc.M109.058305.
62. Douglas JL, Viswanathan K, McCarroll MN, Gustin JK, Fruh K, Moses AV. 2009. Vpu directs the degradation of the human immunodeficiency virus restriction factor BST-2/Tetherin via a {beta}TrCPdependent mechanism. J. Virol. 83:7931-7947. http://dx.doi.org/10.1128/JVI.00242-09.
63. Mitchell RS, Katsura C, Skasko MA, Fitzpatrick K, Lau D, Ruiz A, Stephens EB, Margottin-Goguet F, Benarous R, Guatelli JC. 2009. Vpu antagonizes BST-2-mediated restriction of HIV-1 release via beta-TrCP and endo-lysosomal trafficking. PLoS Pathog. 5:e1000450. http://dx.doi.org/10.1371/journal.ppat.1000450.
64. Andrew AJ, Miyagi E, Strebel K. 2011. Differential effects of human immunodeficiency virus type 1 Vpu on the stability of BST-2/tetherin. J. Virol. 85:2611-2619. http://dx.doi.org/10.1128/JVI.02080-10.
65. Goffinet C, Allespach I, Homann S, Tervo HM, Habermann A, Rupp D, Oberbremer L, Kern C, Tibroni N, Welsch S, Krijnse-Locker J, Banting G, Krausslich HG, Fackler OT, Keppler OT. 2009. HIV-1 antagonism of CD317 is species specific and involves Vpu-mediated proteasomal degradation of the restriction factor. Cell Host Microbe 5:285-297. http://dx.doi.org/10.1016/j.chom.2009.01.009.
66. Gupta RK, Hue S, Schaller T, Verschoor E, Pillay D, Towers GJ. 2009. Mutation of a single residue renders human tetherin resistant to HIV-1 Vpu-mediated depletion. PLoS Pathog. 5:e1000443. http://dx.doi.org/10.1371/journal.ppat.1000443.
67. Hauser H, Lopez LA, Yang SJ, Oldenburg JE, Exline CM, Guatelli JC, Cannon PM. 2010. HIV-1 Vpu and HIV-2 Env counteract BST-2/tetherin by sequestration in a perinuclear compartment. Retrovirology 7:51. http://dx.doi.org/10.1186/1742-4690-7-51.
68. Lopez LA, Yang SJ, Exline CM, Rengarajan S, Haworth KG, Cannon PM. 2012. Anti-tetherin activities of HIV-1 Vpu and Ebola virus glycoprotein do not involve removal of tetherin from lipid rafts. J. Virol. 86: 5467-5480. http://dx.doi.org/10.1128/JVI.06280-11.
69. Bhardwaj N, Maldarelli F, Mellors J, Coffin JM. 2014. HIV-1 infection leads to increased transcription of HERV-K(HML-2) proviruses in vivo but not to increased virion production. J. Virol. 23:01623-01614. http://dx.doi.org/10.1128/JVI.01623-14.
70. Contreras-Galindo R, Kaplan MH, Markovitz DM, Lorenzo E, Yamamura Y. 2006. Detection of HERV-K(HML-2) viral RNA in plasma of HIV type 1-infected individuals. AIDS Res. Hum. Retrovir. 22:979-984. http://dx.doi.org/10.1089/aid.2006.22.979.
71. Hohn O, Hanke K, Bannert N. 2013. HERV-K(HML-2), the best preserved family of HERVs: endogenization, expression, and implications in health and disease. Front. Oncol. 3:246. http://dx.doi.org/10.3389/fonc.2013.00246.
72. Ruprecht K, Mayer J, Sauter M, Roemer K, Mueller-Lantzsch N. 2008. Endogenous retroviruses and cancer. Cell. Mol. Life Sci. 65:3366-3382. http://dx.doi.org/10.1007/s00018-008-8496-1.