Serine Phosphorylation of HIV-1 Vpu and Its Binding to Tetherin Regulates Interaction with Clathrin Adaptors

English version České info

Counteraction of tetherin, a host antiviral protein that blocks viral release from infected cells, is an essential attribute of HIV-1 and its related viruses. The HIV-1 accessory protein Vpu binds to tetherin, preventing its incorporation into viral particles, and targets it for ubiquitin-dependent degradation. This involves mis-trafficking of tetherin by a Vpu-dependent mechanism through the engagement of clathrin adaptor proteins. Although structural evidence exists for Vpu and tetherin interacting with clathrin adaptor 1 (AP-1), evidence that it is required for Vpu-mediated tetherin counteraction is still lacking. Tetherin degradation by Vpu also requires an E3 ubiquitin ligase, SCFβTRCP1/2 that binds to phosphorylated serine residues in the Vpu cytoplasmic tail. Again, discrepancies exist about the importance of this interaction in tetherin’s counteraction. Here we show that Vpu phosphorylation, in combination with its physical interaction with tetherin, regulates interaction with both AP-1 and the other major cellular clathrin adaptor, AP-2. These interactions can be decoupled from SCFβTRCP1/2 recruitment, thus indicating clathrin-dependent mis-trafficking as a critical step in tetherin antagonism by Vpu. Additionally, the ability to interact both with AP-1 and AP-2 in a tetherin-dependent manner indicates a redundancy in host cofactors used by Vpu that explains disparate previous observations of its mechanism of action.

Vyšlo v časopise: Serine Phosphorylation of HIV-1 Vpu and Its Binding to Tetherin Regulates Interaction with Clathrin Adaptors. PLoS Pathog 11(8): e32767. doi:10.1371/journal.ppat.1005141
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005141

Souhrn

Zdroje

1. Neil SJ (2013) The antiviral activities of tetherin. Curr Top Microbiol Immunol 371: 67–104. doi: 10.1007/978-3-642-37765-5_3 23686232

2. Jia B, Serra-Moreno R, Neidermyer W, Rahmberg A, Mackey J, et al. (2009) Species-specific activity of SIV Nef and HIV-1 Vpu in overcoming restriction by tetherin/BST2. PLoS Pathog 5: e1000429. doi: 10.1371/journal.ppat.1000429 19436700

3. 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. doi: 10.1128/JVI.01515-09 19740980

4. Neil SJ, Zang T, Bieniasz PD (2008) Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 451: 425–430. doi: 10.1038/nature06553 18200009

5. Van Damme N, Goff D, Katsura C, Jorgenson RL, Mitchell R, et al. (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. doi: 10.1016/j.chom.2008.03.001 18342597

6. Zhang F, Landford WN, Ng M, McNatt MW, Bieniasz PD, et al. (2011) SIV Nef proteins recruit the AP-2 complex to antagonize Tetherin and facilitate virion release. PLoS Pathog 7: e1002039. doi: 10.1371/journal.ppat.1002039 21625568

7. Perez-Caballero D, Zang T, Ebrahimi A, McNatt MW, Gregory DA, et al. (2009) Tetherin inhibits HIV-1 release by directly tethering virions to cells. Cell 139: 499–511. doi: 10.1016/j.cell.2009.08.039 19879838

8. Venkatesh S, Bieniasz PD (2013) Mechanism of HIV-1 virion entrapment by tetherin. PLoS Pathog 9: e1003483. doi: 10.1371/journal.ppat.1003483 23874200

9. Alvarez RA, Hamlin RE, Monroe A, Moldt B, Hotta MT, et al. (2014) HIV-1 Vpu antagonism of tetherin inhibits antibody-dependent cellular cytotoxic responses by natural killer cells. J Virol 88: 6031–6046. doi: 10.1128/JVI.00449-14 24623433

10. Arias JF, Heyer LN, von Bredow B, Weisgrau KL, Moldt B, et al. (2014) Tetherin antagonism by Vpu protects HIV-infected cells from antibody-dependent cell-mediated cytotoxicity. Proc Natl Acad Sci U S A 111: 6425–6430. doi: 10.1073/pnas.1321507111 24733916

11. Pham TN, Lukhele S, Hajjar F, Routy JP, Cohen EA (2014) HIV Nef and Vpu protect HIV-infected CD4+ T cells from antibody-mediated cell lysis through down-modulation of CD4 and BST2. Retrovirology 11: 15. doi: 10.1186/1742-4690-11-15 24498878

12. Veillette M, Desormeaux A, Medjahed H, Gharsallah NE, Coutu M, et al. (2014) Interaction with cellular CD4 exposes HIV-1 envelope epitopes targeted by antibody-dependent cell-mediated cytotoxicity. J Virol 88: 2633–2644. doi: 10.1128/JVI.03230-13 24352444

13. Cocka LJ, Bates P (2012) Identification of alternatively translated Tetherin isoforms with differing antiviral and signaling activities. PLoS Pathog 8: e1002931. doi: 10.1371/journal.ppat.1002931 23028328

14. 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. doi: 10.1016/j.chom.2012.10.007 23159053

15. Galao RP, Pickering S, Curnock R, Neil SJ (2014) Retroviral Retention Activates a Syk-Dependent HemITAM in Human Tetherin. Cell Host Microbe 16: 291–303. doi: 10.1016/j.chom.2014.08.005 25211072

16. Tokarev A, Suarez M, Kwan W, Fitzpatrick K, Singh R, et al. (2013) Stimulation of NF-kappaB Activity by the HIV Restriction Factor BST2. J Virol 87: 2046–2057. doi: 10.1128/JVI.02272-12 23221546

17. 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. 17940069

18. McNatt MW, Zang T, Bieniasz PD (2013) Vpu binds directly to tetherin and displaces it from nascent virions. PLoS Pathog 9: e1003299. doi: 10.1371/journal.ppat.1003299 23633949

19. Skasko M, Wang Y, Tian Y, Tokarev A, Munguia J, et al. (2012) HIV-1 Vpu protein antagonizes innate restriction factor BST-2 via lipid-embedded helix-helix interactions. J Biol Chem 287: 58–67. doi: 10.1074/jbc.M111.296772 22072710

20. 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. doi: 10.1128/JVI.01699-10 20926557

21. Agromayor M, Soler N, Caballe A, Kueck T, Freund SM, et al. (2012) The UBAP1 subunit of ESCRT-I interacts with ubiquitin via a SOUBA domain. Structure 20: 414–428. doi: 10.1016/j.str.2011.12.013 22405001

22. Janvier K, Pelchen-Matthews A, Renaud JB, Caillet M, Marsh M, et al. (2011) The ESCRT-0 component HRS is required for HIV-1 Vpu-mediated BST-2/tetherin down-regulation. PLoS Pathog 7: e1001265. doi: 10.1371/journal.ppat.1001265 21304933

23. Douglas JL, Viswanathan K, McCarroll MN, Gustin JK, Fruh K, et al. (2009) Vpu directs the degradation of the human immunodeficiency virus restriction factor BST-2/Tetherin via a {beta}TrCP-dependent mechanism. J Virol 83: 7931–7947. doi: 10.1128/JVI.00242-09 19515779

24. Mangeat B, Gers-Huber G, Lehmann M, Zufferey M, Luban J, et al. (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. doi: 10.1371/journal.ppat.1000574 19730691

25. Mitchell RS, Katsura C, Skasko MA, Fitzpatrick K, Lau D, et al. (2009) Vpu antagonizes BST-2-mediated restriction of HIV-1 release via beta-TrCP and endo-lysosomal trafficking. PLoS Pathog 5: e1000450. doi: 10.1371/journal.ppat.1000450 19478868

26. Schubert U, Schneider T, Henklein P, Hoffmann K, Berthold E, et al. (1992) Human-immunodeficiency-virus-type-1-encoded Vpu protein is phosphorylated by casein kinase II. Eur J Biochem 204: 875–883. 1541298

27. Schubert U, Henklein P, Boldyreff B, Wingender E, Strebel K, et al. (1994) The human immunodeficiency virus type 1 encoded Vpu protein is phosphorylated by casein kinase-2 (CK-2) at positions Ser52 and Ser56 within a predicted alpha-helix-turn-alpha-helix-motif. J Mol Biol 236: 16–25. 8107101

28. Margottin F, Bour SP, Durand H, Selig L, Benichou S, et al. (1998) A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif. Mol Cell 1: 565–574. 9660940

29. Tokarev AA, Munguia J, Guatelli JC (2011) Serine-threonine ubiquitination mediates downregulation of BST-2/tetherin and relief of restricted virion release by HIV-1 Vpu. J Virol 85: 51–63. doi: 10.1128/JVI.01795-10 20980512

30. 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. doi: 10.1128/JVI.02080-10 21191020

31. Schubert U, Strebel K (1994) Differential activities of the human immunodeficiency virus type 1-encoded Vpu protein are regulated by phosphorylation and occur in different cellular compartments. J Virol 68: 2260–2271. 8139011

32. Tervo HM, Homann S, Ambiel I, Fritz JV, Fackler OT, et al. (2011) beta-TrCP is dispensable for Vpu's ability to overcome the CD317/Tetherin-imposed restriction to HIV-1 release. Retrovirology 8: 9. doi: 10.1186/1742-4690-8-9 21310048

33. Schmidt S, Fritz JV, Bitzegeio J, Fackler OT, Keppler OT (2011) HIV-1 Vpu blocks recycling and biosynthetic transport of the intrinsic immunity factor CD317/tetherin to overcome the virion release restriction. MBio 2: e00036–00011. doi: 10.1128/mBio.00036-11 21610122

34. Pickering S, Hue S, Kim EY, Reddy S, Wolinsky SM, et al. (2014) Preservation of tetherin and CD4 counter-activities in circulating Vpu alleles despite extensive sequence variation within HIV-1 infected individuals. PLoS Pathog 10: e1003895. doi: 10.1371/journal.ppat.1003895 24465210

35. Dube M, Paquay C, Roy BB, Bego MG, Mercier J, et al. (2011) HIV-1 Vpu antagonizes BST-2 by interfering mainly with the trafficking of newly synthesized BST-2 to the cell surface. Traffic 12: 1714–1729. doi: 10.1111/j.1600-0854.2011.01277.x 21902775

36. Kueck T, Neil SJ (2012) A cytoplasmic tail determinant in HIV-1 Vpu mediates targeting of tetherin for endosomal degradation and counteracts interferon-induced restriction. PLoS Pathog 8: e1002609. doi: 10.1371/journal.ppat.1002609 22479182

37. Bonifacino JS, Traub LM (2003) Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu Rev Biochem 72: 395–447. 12651740

38. Lau D, Kwan W, Guatelli J (2011) Role of the endocytic pathway in the counteraction of BST-2 by human lentiviral pathogens. J Virol 85: 9834–9846. doi: 10.1128/JVI.02633-10 21813615

39. Jia X, Weber E, Tokarev A, Lewinski M, Rizk M, et al. (2014) Structural basis of HIV-1 Vpu-mediated BST2 antagonism via hijacking of the clathrin adaptor protein complex 1. Elife 3: e02362. doi: 10.7554/eLife.02362 24843023

40. Weinelt J, Neil SJ (2014) Differential sensitivities of tetherin isoforms to counteraction by primate lentiviruses. J Virol 88: 5845–5858. doi: 10.1128/JVI.03818-13 24623426

41. Serra-Moreno R, Jia B, Breed M, Alvarez X, Evans DT (2011) Compensatory changes in the cytoplasmic tail of gp41 confer resistance to tetherin/BST-2 in a pathogenic nef-deleted SIV. Cell Host Microbe 9: 46–57. doi: 10.1016/j.chom.2010.12.005 21238946

42. Zhang F, Wilson SJ, Landford WC, Virgen B, Gregory D, et al. (2009) Nef proteins from simian immunodeficiency viruses are tetherin antagonists. Cell Host Microbe 6: 54–67. doi: 10.1016/j.chom.2009.05.008 19501037

43. Mauxion F, Le Borgne R, Munier-Lehmann H, Hoflack B (1996) A casein kinase II phosphorylation site in the cytoplasmic domain of the cation-dependent mannose 6-phosphate receptor determines the high affinity interaction of the AP-1 Golgi assembly proteins with membranes. J Biol Chem 271: 2171–2178. 8567675

44. McDonald B, Martin-Serrano J (2008) Regulation of Tsg101 expression by the steadiness box: a role of Tsg101-associated ligase. Mol Biol Cell 19: 754–763. 18077552

45. Martin-Serrano J, Neil SJ (2011) Host factors involved in retroviral budding and release. Nat Rev Microbiol 9: 519–531. doi: 10.1038/nrmicro2596 21677686

46. Hirano S, Kawasaki M, Ura H, Kato R, Raiborg C, et al. (2006) Double-sided ubiquitin binding of Hrs-UIM in endosomal protein sorting. Nat Struct Mol Biol 13: 272–277. 16462748

47. Tokarev A, Guatelli J (2011) Misdirection of membrane trafficking by HIV-1 Vpu and Nef: Keys to viral virulence and persistence. Cell Logist 1: 90–102. 21922073

48. Miyagi E, Andrew AJ, Kao S, Strebel K (2009) Vpu enhances HIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletion. Proc Natl Acad Sci U S A 106: 2868–2873. doi: 10.1073/pnas.0813223106 19196977

49. Coadou G, Evrard-Todeschi N, Gharbi-Benarous J, Benarous R, Girault JP (2002) HIV-1 encoded virus protein U (Vpu) solution structure of the 41–62 hydrophilic region containing the phosphorylated sites Ser52 and Ser56. Int J Biol Macromol 30: 23–40. 11893391

50. Coadou G, Gharbi-Benarous J, Megy S, Bertho G, Evrard-Todeschi N, et al. (2003) NMR studies of the phosphorylation motif of the HIV-1 protein Vpu bound to the F-box protein beta-TrCP. Biochemistry 42: 14741–14751. 14674748

51. Willbold D, Hoffmann S, Rosch P (1997) Secondary structure and tertiary fold of the human immunodeficiency virus protein U (Vpu) cytoplasmic domain in solution. Eur J Biochem 245: 581–588. 9182993

52. Wittlich M, Koenig BW, Stoldt M, Schmidt H, Willbold D (2009) NMR structural characterization of HIV-1 virus protein U cytoplasmic domain in the presence of dodecylphosphatidylcholine micelles. FEBS J 276: 6560–6575. doi: 10.1111/j.1742-4658.2009.07363.x 19804408

53. Jafari M, Guatelli J, Lewinski MK (2014) Activities of transmitted/founder and chronic clade B HIV-1 Vpu and a C-terminal polymorphism specifically affecting virion release. J Virol 88: 5062–5078. doi: 10.1128/JVI.03472-13 24574397

54. Wittlich M, Koenig BW, Willbold D (2008) Structural consequences of phosphorylation of two serine residues in the cytoplasmic domain of HIV-1 VpU. J Pept Sci 14: 804–810. doi: 10.1002/psc.1004 18186541

55. Miyakawa K, Sawasaki T, Matsunaga S, Tokarev A, Quinn G, et al. (2012) Interferon-induced SCYL2 limits release of HIV-1 by triggering PP2A-mediated dephosphorylation of the viral protein Vpu. Sci Signal 5: ra73. doi: 10.1126/scisignal.2003212 23047923

56. Serra-Moreno R, Zimmermann K, Stern LJ, Evans DT (2013) Tetherin/BST-2 antagonism by Nef depends on a direct physical interaction between Nef and tetherin, and on clathrin-mediated endocytosis. PLoS Pathog 9: e1003487. doi: 10.1371/journal.ppat.1003487 23853598

57. Pardieu C, Vigan R, Wilson SJ, Calvi A, Zang T, et al. (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. doi: 10.1371/journal.ppat.1000843 20419159

58. Neil SJ, Eastman SW, Jouvenet N, Bieniasz PD (2006) HIV-1 Vpu promotes release and prevents endocytosis of nascent retrovirus particles from the plasma membrane. PLoS Pathog 2: e39. 16699598

59. Martin-Serrano J, Yarovoy A, Perez-Caballero D, Bieniasz PD (2003) Divergent retroviral late-budding domains recruit vacuolar protein sorting factors by using alternative adaptor proteins. Proc Natl Acad Sci U S A 100: 12414–12419. 14519844

60. Maldarelli F, Chen MY, Willey RL, Strebel K (1993) Human immunodeficiency virus type 1 Vpu protein is an oligomeric type I integral membrane protein. J Virol 67: 5056–5061. 8331740

61. Roux KJ, Kim DI, Raida M, Burke B (2012) A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells. J Cell Biol 196: 801–810. doi: 10.1083/jcb.201112098 22412018