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  • Review Article
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TRIM family proteins: retroviral restriction and antiviral defence

Nature Reviews Microbiology volume 3, pages 799–808 (2005)Cite this article

Key Points

  • The tripartite motif (TRIM) family is a wide and well conserved family of proteins characterized by a tripartite structure comprising a RING domain, one or two B-boxes and a predicted coiled-coil region. In addition, most TRIM proteins have additional C-terminal domains of various kinds.

  • TRIM19, better known as PML (for promyelocytic leukaemia protein) forms nuclear structures referred to as nuclear bodies. Proteins encoded by various and unrelated viruses have been shown to target PML and to cause the disruption of nuclear bodies, suggesting that these structures might represent an antiviral barrier.

  • TRIM19 has been proposed to be involved in interferon-mediated antiviral response against several viruses, but its direct implication remains controversial.

  • TRIM5α has been recently shown to be responsible for the resistance of primate cells to diverse retrovirus infection. It blocks an early step of retroviral infection prior to reverse transcription. Like its murine cousin, Fv1, TRIM5α restriction is believed to target the capsid protein.

  • How TRIM5α blocks an early step of retroviral replication is still unknown. Diverse hypotheses are being explored. TRIM5α could interfere with the disassembly of viral cores, sequester them in a subcellular compartment, induce their degradation during transit across the cytoplasm or prevent some vital interaction between cellular proteins and viral components.

  • Although very few TRIM proteins have been individually studied, other members of this family have been reported to interfere with viral replication, such as TRIM1 and TRIM22, suggesting viral interference might be a general characteristic of the whole family.

  • The capacity of TRIMs to form high-order molecular-weight structures located in different cellular compartments and their capacity to recruit multiple cellular proteins would allow them to efficiently counteract cellular infection by a wide array of viruses. These observations lead us to discuss the possibility that the TRIM family might represent a new class of antiviral proteins involved in innate immunity.

Abstract

Members of the tripartite motif (TRIM) protein family are involved in various cellular processes, including cell proliferation, differentiation, development, oncogenesis and apoptosis. Some TRIM proteins display antiviral properties, targeting retroviruses in particular. The potential activity of TRIM19, better known as promyelocytic leukaemia protein, against several viruses has been well documented and, recently, TRIM5α has been identified as the factor responsible for the previously described Lv1 and Ref1 antiretroviral activities. There is also evidence indicating that other TRIM proteins can influence viral replication. These findings are reviewed here, and the possibility that TRIMs represent a new and widespread class of antiviral proteins involved in innate immunity is also considered.

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Figure 1: Human tripartite motif (TRIM) proteins.
Figure 2: Splicing variants of human TRIM5 and TRIM19.
Figure 3: Tripartite motif (TRIM) proteins interfering with the retroviral replicative cycle.

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References

  1. Isaacs, A. & Burke, D. C. Mode of action of interferon. Nature 182, 1073–1074 (1958).

    Article  CAS  PubMed  Google Scholar 

  2. Medzhitov, R., Preston-Hurlburt, P. & Janeway, C. A. Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Goff, S. P. Retrovirus restriction factors. Mol. Cell 16, 849–859 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Harris, R. S. & Liddament, M. T. Retroviral restriction by APOBEC proteins. Nature Rev. Immunol. 4, 868–877 (2004).

    Article  CAS  Google Scholar 

  5. Voinnet, O. Induction and suppression of RNA silencing: insights from viral infections. Nature Rev. Genet. 6, 206–220 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Gao, G., Guo, X. & Goff, S. P. Inhibition of retroviral RNA production by ZAP, a CCCH-type zinc finger protein. Science 297, 1703–1706 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Reddy, B. A., Kloc, M. & Etkin, L. The cloning and characterization of a maternally expressed novel zinc finger nuclear phosphoprotein (xnf7) in Xenopus laevis. Dev. Biol. 148, 107–116 (1991). Cloning of the first TRIM.

    Article  CAS  PubMed  Google Scholar 

  8. Reymond, A. et al. The tripartite motif family identifies cell compartments. EMBO J. 20, 2140–2151 (2001). Pioneering characterization of the TRIM family.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ota, T. et al. Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature Genet. 36, 40–45 (2004).

    Article  PubMed  Google Scholar 

  10. Strausberg, R. L. et al. Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc. Natl Acad. Sci. USA 99, 16899–16903 (2002).

    Article  PubMed  Google Scholar 

  11. Miyamoto, K. et al. RING finger, B-box, and coiled-coil (RBCC) protein expression in branchial epithelial cells of Japanese eel, Anguilla japonica. Eur. J. Biochem. 269, 6152–6161 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. C. elegans Sequencing Consortium. Genome sequence of the nematode C. elegans: a platform for investigating biology. Science 282, 2012–2018 (1998).

  13. Saurin, A. J., Borden, K. L., Boddy, M. N. & Freemont, P. S. Does this have a familiar RING? Trends Biochem. Sci. 21, 208–214 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Lovering, R. et al. Identification and preliminary characterization of a protein motif related to the zinc finger. Proc. Natl Acad. Sci. USA 90, 2112–2116 (1993). Identification of the first RING domain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Borden, K. L. RING domains: master builders of molecular scaffolds? J. Mol. Biol. 295, 1103–1112 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Freemont, P. S. RING for destruction? Curr. Biol. 10, R84–R87 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Joazeiro, C. A. & Weissman, A. M. RING finger proteins: mediators of ubiquitin ligase activity. Cell 102, 549–552 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Xu, L. et al. BTBD1 and BTBD2 colocalize to cytoplasmic bodies with the RBCC/tripartite motif protein, TRIM5δ. Exp. Cell Res. 288, 84–93 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Trockenbacher, A. et al. MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation. Nature Genet. 29, 287–294 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Urano, T. et al. Efp targets 14-3-3σ for proteolysis and promotes breast tumour growth. Nature 417, 871–875 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Horn, E. J. et al. RING protein Trim32 associated with skin carcinogenesis has anti-apoptotic and E3-ubiquitin ligase properties. Carcinogenesis 25, 157–167 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Vichi, A., Payne, D. M., Pacheco-Rodriguez, G., Moss, J. & Vaughan, M. E3 ubiquitin ligase activity of the trifunctional ARD1 (ADP-ribosylation factor domain protein 1). Proc. Natl Acad. Sci. USA 102, 1945–1950 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Reddy, B. A., Etkin, L. D. & Freemont, P. S. A novel zinc finger coiled-coil domain in a family of nuclear proteins. Trends Biochem. Sci. 17, 344–345 (1992). Provides the first characterization of a coiled-coil domain.

    Article  CAS  PubMed  Google Scholar 

  24. Borden, K. L. et al. In vivo and in vitro characterization of the B1 and B2 zinc-binding domains from the acute promyelocytic leukemia protooncoprotein PML. Proc. Natl Acad. Sci. USA 93, 1601–1606 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cao, T., Borden, K. L., Freemont, P. S. & Etkin, L. D. Involvement of the rfp tripartite motif in protein—protein interactions and subcellular distribution. J. Cell Sci. 110, 1563–1571 (1997).

    CAS  PubMed  Google Scholar 

  26. Borden, K. L. et al. The solution structure of the RING finger domain from the acute promyelocytic leukaemia proto-oncoprotein PML. EMBO J. 14, 1532–1541 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Peng, H. et al. Reconstitution of the KRAB-KAP-1 repressor complex: a model system for defining the molecular anatomy of RING-B box-coiled-coil domain-mediated protein—protein interactions. J. Mol. Biol. 295, 1139–1162 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Ponting, C., Schultz, J. & Bork, P. SPRY domains in ryanodine receptors (Ca2+-release channels). Trends Biochem. Sci. 22, 193–194 (1997). The first report to identify SPRY domains.

    Article  CAS  PubMed  Google Scholar 

  29. Henry, J., Mather, I. H., McDermott, M. F. & Pontarotti, P. B30.2-like domain proteins: update and new insights into a rapidly expanding family of proteins. Mol. Biol. Evol. 15, 1696–1705 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Vernet, C. et al. Evolutionary study of multigenic families mapping close to the human MHC class I region. J. Mol. Evol. 37, 600–612 (1993).

    Article  CAS  PubMed  Google Scholar 

  31. Hilton, D. J. et al. Twenty proteins containing a C-terminal SOCS box form five structural classes. Proc. Natl Acad. Sci. USA 95, 114–119 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Aasland, R., Gibson, T. J. & Stewart, A. F. The PHD finger: implications for chromatin-mediated transcriptional regulation. Trends Biochem. Sci. 20, 56–59 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. Le Douarin, B. et al. A possible involvement of TIF1 α and TIF1 β in the epigenetic control of transcription by nuclear receptors. EMBO J. 15, 6701–6715 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Venturini, L. et al. TIF1γ, a novel member of the transcriptional intermediary factor 1 family. Oncogene 18, 1209–1217 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. The French FMF Consortium. A candidate gene for familial Mediterranean fever. Nature Genet. 17, 25–31 (1997).

  36. Quaderi, N. A. et al. Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Nature Genet. 17, 285–291 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Frosk, P. et al. Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene. Am. J. Hum. Genet. 70, 663–672 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Avela, K. et al. Gene encoding a new RING-B-box-coiled-coil protein is mutated in mulibrey nanism. Nature Genet. 25, 298–301 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. de The, H. et al. The PML-RARα fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66, 675–684 (1991).

    Article  CAS  PubMed  Google Scholar 

  40. Kakizuka, A. et al. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARα with a novel putative transcription factor, PML. Cell 66, 663–674 (1991).

    Article  CAS  PubMed  Google Scholar 

  41. Goddard, A. D., Borrow, J., Freemont, P. S. & Solomon, E. Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia. Science 254, 1371–1374 (1991). References 39–41 report the identification of PML as a PML–RARα fusion protein.

    Article  CAS  PubMed  Google Scholar 

  42. Takahashi, M., Inaguma, Y., Hiai, H. & Hirose, F. Developmentally regulated expression of a human 'finger'-containing gene encoded by the 5′ half of the ret transforming gene. Mol. Cell Biol. 8, 1853–1856 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Le Douarin, B. et al. The N-terminal part of TIF1, a putative mediator of the ligand-dependent activation function (AF-2) of nuclear receptors, is fused to B-raf in the oncogenic protein T18. EMBO J. 14, 2020–2033 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Stremlau, M. et al. The cytoplasmic body component TRIM5α restricts HIV-1 infection in Old World monkeys. Nature 427, 848–853 (2004). Direct demonstration of the anti-HIV activity of simian TRIM5α.

    Article  CAS  PubMed  Google Scholar 

  45. Hatziioannou, T., Perez-Caballero, D., Yang, A., Cowan, S. & Bieniasz, P. D. Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5α. Proc. Natl Acad. Sci. USA 101, 10774–10779 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Keckesova, Z., Ylinen, L. M. & Towers, G. J. The human and African green monkey TRIM5α genes encode Ref1 and Lv1 retroviral restriction factor activities. Proc. Natl Acad. Sci. USA 101, 10780–10785 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Perron, M. J. et al. TRIM5α mediates the postentry block to N-tropic murine leukemia viruses in human cells. Proc. Natl Acad. Sci. USA 101, 11827–11832 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yap, M. W., Nisole, S., Lynch, C. & Stoye, J. P. Trim5α protein restricts both HIV-1 and murine leukemia virus. Proc. Natl Acad. Sci. USA 101, 10786–10791 (2004). References 45–48 identify TRIM5α as the factor responsible for Ref1 and Lv1 restriction activities.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tissot, C. & Mechti, N. Molecular cloning of a new interferon-induced factor that represses human immunodeficiency virus type 1 long terminal repeat expression. J. Biol. Chem. 270, 14891–14898 (1995).

    Article  CAS  PubMed  Google Scholar 

  50. Hofmann, T. G. & Will, H. Body language: the function of PML nuclear bodies in apoptosis regulation. Cell Death Differ. 10, 1290–1299 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Kentsis, A. et al. The RING domains of the promyelocytic leukemia protein PML and the arenaviral protein Z repress translation by directly inhibiting translation initiation factor eIF4E. J. Mol. Biol. 312, 609–623 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Pearson, M. et al. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406, 207–210 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Wang, Z. G. et al. Role of PML in cell growth and the retinoic acid pathway. Science 279, 1547–1551 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Lin, H. K., Bergmann, S. & Pandolfi, P. P. Cytoplasmic PML function in TGF-β signalling. Nature 431, 205–211 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Koken, M. H. et al. The t(15;17) translocation alters a nuclear body in a retinoic acid-reversible fashion. EMBO J. 13, 1073–1083 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Muller, S., Matunis, M. J. & Dejean, A. Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus. EMBO J. 17, 61–70 (1998). First evidence for the involvement of SUMO in the control of PML localization.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ishov, A. M. et al. PML is critical for ND10 formation and recruits the PML-interacting protein daxx to this nuclear structure when modified by SUMO-1. J. Cell Biol. 147, 221–234 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sternsdorf, T., Jensen, K. & Will, H. Evidence for covalent modification of the nuclear dot-associated proteins PML and Sp100 by PIC1/SUMO-1. J. Cell Biol. 139, 1621–1634 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Dyck, J. A. et al. A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein. Cell 76, 333–343 (1994).

    Article  CAS  PubMed  Google Scholar 

  60. Weis, K. et al. Retinoic acid regulates aberrant nuclear localization of PML–RARα in acute promyelocytic leukemia cells. Cell 76, 345–356 (1994).

    Article  CAS  PubMed  Google Scholar 

  61. Zhu, J., Chen, Z., Lallemand-Breitenbach, V. & de The, H. How acute promyelocytic leukaemia revived arsenic. Nature Rev. Cancer 2, 705–713 (2002).

    Article  CAS  Google Scholar 

  62. Zhu, J. et al. Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia. Proc. Natl Acad. Sci. USA 94, 3978–3983 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lallemand-Breitenbach, V. et al. Role of promyelocytic leukemia (PML) sumolation in nuclear body formation, 11S proteasome recruitment, and As2O3-induced PML or PML/retinoic acid receptor α degradation. J. Exp. Med. 193, 1361–1371 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Boutell, C., Orr, A. & Everett, R. D. PML residue lysine 160 is required for the degradation of PML induced by herpes simplex virus type 1 regulatory protein ICP0. J. Virol. 77, 8686–8694 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Borden, K. L. Pondering the promyelocytic leukemia protein (PML) puzzle: possible functions for PML nuclear bodies. Mol. Cell Biol. 22, 5259–5269 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Stadler, M. et al. Transcriptional induction of the PML growth suppressor gene by interferons is mediated through an ISRE and a GAS element. Oncogene 11, 2565–2573 (1995).

    CAS  PubMed  Google Scholar 

  67. Chelbi-Alix, M. K. et al. Induction of the PML protein by interferons in normal and APL cells. Leukemia 9, 2027–2033 (1995).

    CAS  PubMed  Google Scholar 

  68. Lavau, C. et al. The acute promyelocytic leukaemia-associated PML gene is induced by interferon. Oncogene 11, 871–876 (1995).

    CAS  PubMed  Google Scholar 

  69. Katze, M. G., He, Y. & Gale, M. Jr. Viruses and interferon: a fight for supremacy. Nature Rev. Immunol. 2, 675–687 (2002).

    Article  CAS  Google Scholar 

  70. Chelbi-Alix, M. K., Quignon, F., Pelicano, L., Koken, M. H. & de The, H. Resistance to virus infection conferred by the interferon-induced promyelocytic leukemia protein. J. Virol. 72, 1043–1051 (1998). First evidence for an antiviral activity of PML.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Asper, M. et al. Inhibition of different Lassa virus strains by α and γ interferons and comparison with a less pathogenic arenavirus. J. Virol. 78, 3162–3169 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Turelli, P. et al. Cytoplasmic recruitment of INI1 and PML on incoming HIV preintegration complexes: interference with early steps of viral replication. Mol. Cell 7, 1245–1254 (2001). Important but controversial paper describing the inhibition of HIV by PML.

    Article  CAS  PubMed  Google Scholar 

  73. Bell, P., Montaner, L. J. & Maul, G. G. Accumulation and intranuclear distribution of unintegrated human immunodeficiency virus type 1 DNA. J. Virol. 75, 7683–7691 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Berthoux, L. et al. As2O3 enhances retroviral reverse transcription and counteracts Ref1 antiviral activity. J. Virol. 77, 3167–3180 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Regad, T. et al. PML mediates the interferon-induced antiviral state against a complex retrovirus via its association with the viral transactivator. EMBO J. 20, 3495–3505 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Meiering, C. D. & Linial, M. L. The promyelocytic leukemia protein does not mediate foamy virus latency in vitro. J. Virol. 77, 2207–2213 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Borden, K. L., Campbell Dwyer, E. J. & Salvato, M. S. An arenavirus RING (zinc-binding) protein binds the oncoprotein promyelocyte leukemia protein (PML) and relocates PML nuclear bodies to the cytoplasm. J. Virol. 72, 758–766 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Blondel, D. et al. Rabies virus P and small P products interact directly with PML and reorganize PML nuclear bodies. Oncogene 21, 7957–7970 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Maul, G. G., Guldner, H. H. & Spivack, J. G. Modification of discrete nuclear domains induced by herpes simplex virus type 1 immediate early gene 1 product (ICP0). J. Gen. Virol. 74, 2679–2690 (1993). Pioneering paper reporting the disruption of NBs by a viral protein.

    Article  CAS  PubMed  Google Scholar 

  80. Everett, R. D. & Maul, G. G. HSV-1 IE protein Vmw110 causes redistribution of PML. EMBO J. 13, 5062–5069 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chelbi-Alix, M. K. & de The, H. Herpes virus induced proteasome-dependent degradation of the nuclear bodies-associated PML and Sp100 proteins. Oncogene 18, 935–941 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. Muller, S. & Dejean, A. Viral immediate-early proteins abrogate the modification by SUMO-1 of PML and Sp100 proteins, correlating with nuclear body disruption. J. Virol. 73, 5137–5143 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Boutell, C., Sadis, S. & Everett, R. D. Herpes simplex virus type 1 immediate-early protein ICP0 and is isolated RING finger domain act as ubiquitin E3 ligases in vitro. J. Virol. 76, 841–850 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hagglund, R. & Roizman, B. Characterization of the novel E3 ubiquitin ligase encoded in exon 3 of herpes simplex virus-1-infected cell protein 0. Proc. Natl Acad. Sci. USA 99, 7889–7894 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Boutell, C. & Everett, R. D. The herpes simplex virus type 1 (HSV-1) regulatory protein ICP0 interacts with and ubiquitinates p53. J. Biol. Chem. 278, 36596–36602 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Gu, H. & Roizman, B. The degradation of promyelocytic leukemia and Sp100 proteins by herpes simplex virus 1 is mediated by the ubiquitin-conjugating enzyme UbcH5a. Proc. Natl Acad. Sci. USA 100, 8963–8968 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lopez, P., Jacob, R. J. & Roizman, B. Overexpression of promyelocytic leukemia protein precludes the dispersal of ND10 structures and has no effect on accumulation of infectious herpes simplex virus 1 or its proteins. J. Virol. 76, 9355–9367 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Chee, A. V., Lopez, P., Pandolfi, P. P. & Roizman, B. Promyelocytic leukemia protein mediates interferon-based anti-herpes simplex virus 1 effects. J. Virol. 77, 7101–7105 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Parkinson, J. & Everett, R. D. αherpesvirus proteins related to herpes simplex virus type 1 ICP0 affect cellular structures and proteins. J. Virol. 74, 10006–10017 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lilly, F. Fv-2: Identification and location of a second gene governing the spleen focus response to Friend leukemia virus in mice. J. Natl Cancer Inst. 45, 163–169 (1970).

    CAS  PubMed  Google Scholar 

  91. Hartley, J. W., Rowe, W. P. & Huebner, R. J. Host-range restrictions of murine leukemia viruses in mouse embryo cell cultures. J. Virol. 5, 221–225 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. DesGroseillers, L. & Jolicoeur, P. Physical mapping of the Fv-1 tropism host range determinant of BALB/c murine leukemia viruses. J. Virol. 48, 685–696 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Kozak, C. A. & Chakraborti, A. Single amino acid changes in the murine leukemia virus capsid protein gene define the target of Fv1 resistance. Virology 225, 300–305 (1996).

    Article  CAS  PubMed  Google Scholar 

  94. Stoye, J. P. Fv1, the mouse retrovirus resistance gene. Rev. Sci. Tech. 17, 269–277 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Best, S., Le Tissier, P., Towers, G. & Stoye, J. P. Positional cloning of the mouse retrovirus restriction gene Fv1. Nature 382, 826–829 (1996). Cloning of Fv1, the prototype of restriction factors.

    Article  CAS  PubMed  Google Scholar 

  96. Cordonnier, A., Casella, J. -F. & Heidmann, T. Isolation of novel human endogenous retrovirus-like elements with foamy virus-related pol sequence. J. Virol. 69, 5890–5897 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Goff, S. P. Operating under a Gag order: a block against incoming virus by the Fv1 gene. Cell 86, 691–693 (1996).

    Article  CAS  PubMed  Google Scholar 

  98. Benit, L. et al. Cloning of a new murine endogenous retrovirus, MuERV-L, with strong similarity to the human HERV-L element and with a gag coding sequence closely related to the Fv1 restriction gene. J. Virol. 71, 5652–5657 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Towers, G. et al. A conserved mechanism of retrovirus restriction in mammals. Proc. Natl Acad. Sci. USA 97, 12295–12299 (2000). First evidence for the existence of Fv1-like factors in non-murine cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Besnier, C. et al. Characterization of murine leukemia virus restriction in mammals. J. Virol. 77, 13403–13406 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Hofmann, W. et al. Species-specific, postentry barriers to primate immunodeficiency virus infection. J. Virol. 73, 10020–10028 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Besnier, C., Takeuchi, Y. & Towers, G. Restriction of lentivirus in monkeys. Proc. Natl Acad. Sci. USA 99, 11920–11925 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Cowan, S. et al. Cellular inhibitors with Fv1-like activity restrict human and simian immunodeficiency virus tropism. Proc. Natl Acad. Sci. USA 99, 11914–11919 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Munk, C., Brandt, S. M., Lucero, G. & Landau, N. R. A dominant block to HIV-1 replication at reverse transcription in simian cells. Proc. Natl Acad. Sci. USA 99, 13843–13848 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Yap, M. W., Nisole, S. & Stoye, J. P. A single amino acid change in the SPRY domain of human Trim5α leads to HIV-1 restriction. Curr. Biol. 15, 73–78 (2005). A rigorous mapping of restriction determinants within TRIM5α.

    Article  CAS  PubMed  Google Scholar 

  106. Stremlau, M., Perron, M., Welikala, S. & Sodroski, J. Species-specific variation in the B30.2(SPRY) domain of TRIM5α determines the potency of human immunodeficiency virus restriction. J. Virol. 79, 3139–3145 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Haran-Ghera, N., Peled, A., Brightman, B. K. & Fan, H. Lymphomagenesis in AKR. Fv-1b congenic mice. Cancer Res. 53, 3433–3438 (1993).

    CAS  PubMed  Google Scholar 

  108. Sawyer, S. L., Wu, L. I., Emerman, M. & Malik, H. S. Positive selection of primate TRIM5α identifies a critical species-specific retroviral restriction domain. Proc. Natl Acad. Sci. USA 102, 2832–2837 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Song, B. et al. The B30.2(SPRY) domain of the retroviral restriction factor TRIM5α exhibits lineage-specific length and sequence variation in primates. J. Virol. 79, 6111–6121 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Jolicoeur, P. The Fv-1 gene of the mouse and its control of murine leukemia virus replication. Curr. Top. Microbiol. Immunol. 86, 67–122 (1979).

    Article  CAS  PubMed  Google Scholar 

  111. Duran-Troise, G., Bassin, R. H., Rein, A. & Gerwin, B. I. Loss of Fv-1 restriction in Balb/3T3 cells following infection with a single N tropic murine leukemia particle. Cell 10, 479–488 (1977).

    Article  CAS  PubMed  Google Scholar 

  112. Yap, M. W. & Stoye, J. P. Intracellular localisation of Fv1. Virology 307, 76–89 (2003).

    Article  CAS  PubMed  Google Scholar 

  113. Nisole, S., Lynch, C., Stoye, J. P. & Yap, M. W. A Trim5-cyclophilin A fusion protein found in owl monkey kidney cells can restrict HIV-1. Proc. Natl Acad. Sci. USA 101, 13324–13328 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Sayah, D. M., Sokolskaja, E., Berthoux, L. & Luban, J. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature 430, 569–573 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Luban, J., Bossolt, K. L., Franke, E. K., Kalpana, G. V. & Goff, S. P. Human immunodeficiency virus type 1 Gag protein binds to cyclophilins A and B. Cell 73, 1067–1078 (1993).

    Article  CAS  PubMed  Google Scholar 

  116. Gamble, T. R. et al. Crystal structure of human cyclophilin A bound to the amino-terminal domain of HIV-1 capsid. Cell 87, 1285–1294 (1996).

    Article  CAS  PubMed  Google Scholar 

  117. Towers, G. J. et al. Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors. Nature Med. 9, 1138–1143 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. Forshey, B. M., von Schwedler, U., Sundquist, W. I. & Aiken, S. C. Formation of a human immunodeficiency virus type 1 core of optimal stability is crucial for viral replication. J. Virol. 76, 5667–5677 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Dodding, M. P., Bock, M., Yap, M. W. & Stoye, J. P. Capsid processing requirements for abrogation of fv1 and ref1 restriction. J. Virol. 79, 10571–10577 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Mortuza, G. B. et al. High-resolution structure of a retroviral capsid hexameric amino-terminal domain. Nature 431, 481–485 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Berthoux, L., Sebastian, S., Sokolskaja, E. & Luban, J. Lv1 inhibition of human immunodeficiency virus type 1 is counteracted by factors that stimulate synthesis or nuclear translocation of viral cDNA. J. Virol. 78, 11739–11750 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Nisole, S. & Saib, A. Early steps of retrovirus replicative cycle. Retrovirology 1, 9 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Fridell, R. A., Harding, L. S., Bogerd, H. P. & Cullen, B. R. Identification of a novel human zinc finger protein that specifically interacts with the activation domain of lentiviral Tat proteins. Virology 209, 347–357 (1995).

    Article  CAS  PubMed  Google Scholar 

  124. Geiss, G. K. et al. Cellular transcriptional profiling in influenza A virus-infected lung epithelial cells: the role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza. Proc. Natl Acad. Sci. USA 99, 10736–10741 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Wang, Y. et al. TRIM45, a novel human RBCC/TRIM protein, inhibits transcriptional activities of ElK-1 and AP-1. Biochem. Biophys. Res. Commun. 323, 9–16 (2004).

    Article  CAS  PubMed  Google Scholar 

  126. Bjorndal, A. S., Szekely, L. & Elgh, F. Ebola virus infection inversely correlates with the overall expression levels of promyelocytic leukaemia (PML) protein in cultured cells. BMC Microbiol. 3, 6 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Bonilla, W. V. et al. Effects of promyelocytic leukemia protein on virus–host balance. J. Virol. 76, 3810–3818 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Djavani, M. et al. Role of the promyelocytic leukemia protein PML in the interferon sensitivity of lymphocytic choriomeningitis virus. J. Virol. 75, 6204–6208 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank L. Burleigh and V. Lallemand-Breitenbach for critical review of the manuscript. S.N. is supported by the Fondation pour la Recherche Médicale. This work was supported by the Medical Research Council UK and the Agence Nationale de Recherches sur le SIDA.

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Authors and Affiliations

  1. Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7151, Université Paris 7, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, Paris, 75475 cedex 10, France

    Sébastien Nisole & Ali Saïb

  2. Division of Virology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK

    Jonathan P. Stoye

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  1. Sébastien Nisole
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Correspondence to Sébastien Nisole.

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Supplementary information S1 (Table) (PDF 304 kb)

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DATABASES

Entrez

adenovirus type 5

bovine herpesvirus 1

Epstein–Barr virus

equine herpesvirus 1

HFV

HIV-1

HSV-1

MLV

pseudorabies virus

rabies virus

SIV

TRIM10

TRIM15

TRIM18

TRIM20

TRIM26

TRIM27

TRIM31

TRIM32

TRIM37

TRIM38

TRIM39

TRIM40

varicella-zoster virus

VSV

SwissProt

Braf

BZLF1

Fv1

ICP0

ie1

RARα

Sp100

SUMO

Tas

TRIM1

TRIM18

TRIM19

TRIM22

TRIM24

TRIM25

TRIM27

TRIM28

TRIM32

TRIM33

TRIM35

XNF7

Glossary

UBIQUITIN E3 LIGASE

Ubiquitination requires three enzymes: a ubiquitin-activating (E1) enzyme, a ubiquitin-conjugating (E2) enzyme and a ubiquitin-protein ligase (E3) enzyme. Two of the main families of E3s are the HECT-domain-containing enzymes (for example, NEDD4) and RING-domain-containing enzymes (for example, Cbl).

EXON SHUFFLING

The process of non-homologous recombination of exons from different genes.

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Nisole, S., Stoye, J. & Saïb, A. TRIM family proteins: retroviral restriction and antiviral defence. Nat Rev Microbiol 3, 799–808 (2005). https://doi.org/10.1038/nrmicro1248

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