Current HIV/AIDS Reports

, Volume 9, Issue 1, pp 73–80

The Cell Biology of TRIM5α

The Science of HIV (AL Landay, Section Editor)

Abstract

The tripartite motif (TRIM)–containing proteins are involved in many cellular functions such as cell signaling, apoptosis, cell differentiation, and immune modulation. TRIM5 proteins, including TRIM5α and TRIM-Cyp, are known to possess antiretroviral activity against many different retroviruses. Besides being retroviral restriction factors, TRIM5 proteins participate in other cellular functions that have recently emerged in the study of TRIM5α. In this review, we discuss properties of TRIM5α such as cytoplasmic body formation, protein turnover, and trafficking. Also, we discuss recent insights into innate immune modulation mediated by TRIM5α, highlighting the various functions TRIM5α has in cellular processes.

Keywords

rhTRIM5alpha Cytoplasmic bodies HIV-1 Restriction factor Signaling 2 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Stremlau M, Owens CM, Perron MJ, Kiessling M, Autissier P, Sodroski J. The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys. Nature. 2004;427:848–53.PubMedCrossRefGoogle Scholar
  2. 2.
    Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, et al. The tripartite motif family identifies cell compartments. Embo J. 2001;20:2140–51.PubMedCrossRefGoogle Scholar
  3. 3.
    Diaz-Griffero F, Qin XR, Hayashi F, Kigawa T, Finzi A, Sarnak Z, et al. A B-box 2 surface patch important for TRIM5alpha self-association, capsid binding avidity, and retrovirus restriction. J Virol. 2009;83:10737–51.PubMedCrossRefGoogle Scholar
  4. 4.
    Li X, Sodroski J. The TRIM5alpha B-box 2 domain promotes cooperative binding to the retroviral capsid by mediating higher-order self-association. J Virol. 2008;82:11495–502.PubMedCrossRefGoogle Scholar
  5. 5.
    Li X, Song B, Xiang SH, Sodroski J. Functional interplay between the B-box 2 and the B30.2(SPRY) domains of TRIM5alpha. Virology. 2007;366:234–44.PubMedCrossRefGoogle Scholar
  6. 6.
    Adams SR, Campbell RE, Gross LA, Martin BR, Walkup GK, Yao Y, et al. New biarsenical ligands and tetracysteine motifs for protein labeling in vitro and in vivo: synthesis and biological applications. J Am Chem Soc. 2002;124:6063–76.PubMedCrossRefGoogle Scholar
  7. 7.
    Javanbakht H, Yuan W, Yeung DF, Song B, Diaz-Griffero F, Li Y, et al. Characterization of TRIM5alpha trimerization and its contribution to human immunodeficiency virus capsid binding. Virology. 2006;353:234–46.PubMedCrossRefGoogle Scholar
  8. 8.
    Kar AK, Diaz-Griffero F, Li Y, Li X, Sodroski J. Biochemical and biophysical characterization of a chimeric TRIM21-TRIM5alpha protein. J Virol. 2008;82:11669–81.PubMedCrossRefGoogle Scholar
  9. 9.
    Langelier CR, Sandrin V, Eckert DM, Christensen DE, Chandrasekaran V, Alam SL, et al. Biochemical characterization of a recombinant TRIM5alpha protein that restricts human immunodeficiency virus type 1 replication. J Virol. 2008;82:11682–94.PubMedCrossRefGoogle Scholar
  10. 10.
    Mische CC, Javanbakht H, Song B, Diaz-Griffero F, Stremlau M, Strack B, et al. Retroviral restriction factor TRIM5alpha is a trimer. J Virol. 2005;79:14446–50.PubMedCrossRefGoogle Scholar
  11. 11.
    Li X, Yeung DF, Fiegen AM, Sodroski J. Determinants of the Higher Order Association of the Restriction Factor TRIM5{alpha} and Other Tripartite Motif (TRIM) Proteins. J Biol Chem. 2011;286:27959–70.PubMedCrossRefGoogle Scholar
  12. 12.
    Sastri J, O'Connor C, Danielson CM, McRaven M, Perez P, Diaz-Griffero F, et al. Identification of residues within the L2 region of rhesus TRIM5alpha that are required for retroviral restriction and cytoplasmic body localization. Virology. 2010;405:259–66.PubMedCrossRefGoogle Scholar
  13. 13.
    Stremlau M, Perron M, Welikala S, Sodroski J. Species-specific variation in the B30.2(SPRY) domain of TRIM5alpha determines the potency of human immunodeficiency virus restriction. J Virol. 2005;79:3139–45.PubMedCrossRefGoogle Scholar
  14. 14.
    Yap MW, Nisole S, Stoye JP. A single amino acid change in the SPRY domain of human Trim5alpha leads to HIV-1 restriction. Curr Biol. 2005;15:73–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Sawyer SL, Wu LI, Emerman M, Malik HS. Positive selection of primate TRIM5alpha identifies a critical species-specific retroviral restriction domain. Proc Natl Acad Sci U S A. 2005;102:2832–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Johnson WE, Sawyer SL. Molecular evolution of the antiretroviral TRIM5 gene. Immunogenetics. 2009;61:163–76.PubMedCrossRefGoogle Scholar
  17. 17.
    Nakayama EE, Shioda T. Anti-retroviral activity of TRIM5 alpha. Rev Med Virol. 2010;20:77–92.PubMedCrossRefGoogle Scholar
  18. 18.
    Sastri J, Campbell EM. Recent insights into the mechanism and consequences of TRIM5alpha retroviral restriction. AIDS Res Hum Retroviruses. 2011;27:231–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Newman RM, Hall L, Kirmaier A, Pozzi LA, Pery E, Farzan M, et al. Evolution of a TRIM5-CypA splice isoform in old world monkeys. PLoS Pathog. 2008;4:e1000003.PubMedCrossRefGoogle Scholar
  20. 20.
    Sayah DM, Sokolskaja E, Berthoux L, Luban J. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature. 2004;430:569–73.PubMedCrossRefGoogle Scholar
  21. 21.
    Virgen CA, Kratovac Z, Bieniasz PD, Hatziioannou T. Independent genesis of chimeric TRIM5-cyclophilin proteins in two primate species. Proc Natl Acad Sci U S A. 2008;105:3563–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Wilson SJ, Webb BL, Ylinen LM, Verschoor E, Heeney JL, Towers GJ. Independent evolution of an antiviral TRIMCyp in rhesus macaques. Proc Natl Acad Sci U S A. 2008;105:3557–62.PubMedCrossRefGoogle Scholar
  23. 23.
    Diaz-Griffero, F., A. Kar, M. Perron, S. H. Xiang, H. Javanbakht, X. Li, and J. Sodroski. 2007. Modulation of Retroviral Restriction and Proteasome Inhibitor-resistant Turnover by Changes in the TRIM5{alpha} B-box 2 Domain. J Virol.Google Scholar
  24. 24.
    Diaz-Griffero F, Li X, Javanbakht H, Song B, Welikala S, Stremlau M, et al. Rapid turnover and polyubiquitylation of the retroviral restriction factor TRIM5. Virology. 2006;349:300–15.PubMedCrossRefGoogle Scholar
  25. 25.
    Diaz-Griffero F, Vandegraaff N, Li Y, McGee-Estrada K, Stremlau M, Welikala S, et al. Requirements for capsid-binding and an effector function in TRIMCyp-mediated restriction of HIV-1. Virology. 2006;351:404–19.PubMedCrossRefGoogle Scholar
  26. 26.
    Nepveu-Traversy ME, Berube J, Berthoux L. TRIM5alpha and TRIMCyp form apparent hexamers and their multimeric state is not affected by exposure to restriction-sensitive viruses or by treatment with pharmacological inhibitors. Retrovirology. 2009;6:100.PubMedCrossRefGoogle Scholar
  27. 27.
    Diaz-Griffero F, Kar A, Lee M, Stremlau M, Poeschla E, Sodroski J. Comparative requirements for the restriction of retrovirus infection by TRIM5alpha and TRIMCyp. Virology. 2007;369:400–10.PubMedCrossRefGoogle Scholar
  28. 28.
    • Ganser-Pornillos, B. K., V. Chandrasekaran, O. Pornillos, J. G. Sodroski, W. I. Sundquist, and M. Yeager. 2011. Hexagonal assembly of a restricting TRIM5alpha protein. Proc Natl Acad Sci U S A 108:534-9. This paper visualized the TRIM5α lattice, mediated by the ability of TRIM5α to self-associate, which likely forms around restriction-sensitive viral capsids. PubMedCrossRefGoogle Scholar
  29. 29.
    Campbell EM, Dodding MP, Yap MW, Wu X, Gallois-Montbrun S, Malim MH, et al. TRIM5 alpha cytoplasmic bodies are highly dynamic structures. Mol Biol Cell. 2007;18:2102–11.PubMedCrossRefGoogle Scholar
  30. 30.
    • Campbell, E. M., O. Perez, J. L. Anderson, and T. J. Hope. 2008. Visualization of a proteasome-independent intermediate during restriction of HIV-1 by rhesus TRIM5alpha. J Cell Biol 180:549-61. This paper visualized the association between TRIM5α cytoplasmic bodies during restriction, demonstrating that the ability of TRIM5α to self associate around viral complexes, manifested at the formation of cytoplasmic bodies, plays an important role in retroviral restriction. PubMedCrossRefGoogle Scholar
  31. 31.
    Song B, Diaz-Griffero F, Park DH, Rogers T, Stremlau M, Sodroski J. TRIM5alpha association with cytoplasmic bodies is not required for antiretroviral activity. Virology. 2005;343:201–11.PubMedCrossRefGoogle Scholar
  32. 32.
    Perez-Caballero D, Hatziioannou T, Zhang F, Cowan S, Bieniasz PD. Restriction of human immunodeficiency virus type 1 by TRIM-CypA occurs with rapid kinetics and independently of cytoplasmic bodies, ubiquitin, and proteasome activity. J Virol. 2005;79:15567–72.PubMedCrossRefGoogle Scholar
  33. 33.
    • Pertel, T., S. Hausmann, D. Morger, S. Zuger, J. Guerra, J. Lascano, C. Reinhard, F. A. Santoni, P. D. Uchil, L. Chatel, A. Bisiaux, M. L. Albert, C. Strambio-De-Castillia, W. Mothes, M. Pizzato, M. G. Grutter, and J. Luban. 2011. TRIM5 is an innate immune sensor for the retrovirus capsid lattice. Nature 472:361-5. This study identified the connection between the ability of TRIM5 proteins to restrict retroviral infection and its ability to associate with proteins involved in signal transduction, most notably TAK1. PubMedCrossRefGoogle Scholar
  34. 34.
    Tareen SU, Emerman M. Human Trim5alpha has additional activities that are uncoupled from retroviral capsid recognition. Virology. 2011;409:113–20.PubMedCrossRefGoogle Scholar
  35. 35.
    Dyck JA, Maul GG, Miller Jr WH, Chen JD, Kakizuka A, Evans RM. A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein. Cell. 1994;76:333–43.PubMedCrossRefGoogle Scholar
  36. 36.
    Puvion-Dutilleul F, Chelbi-Alix MK, Koken M, Quignon F, Puvion E, de The H. Adenovirus infection induces rearrangements in the intranuclear distribution of the nuclear body-associated PML protein. Exp Cell Res. 1995;218:9–16.PubMedCrossRefGoogle Scholar
  37. 37.
    Weis K, Rambaud S, Lavau C, Jansen J, Carvalho T, Carmo-Fonseca M, et al. Retinoic acid regulates aberrant nuclear localization of PML-RAR alpha in acute promyelocytic leukemia cells. Cell. 1994;76:345–56.PubMedCrossRefGoogle Scholar
  38. 38.
    Lallemand-Breitenbach V, de The H. PML nuclear bodies. Cold Spring Harb Perspect Biol. 2010;2:a000661.PubMedCrossRefGoogle Scholar
  39. 39.
    Everett RD, Chelbi-Alix MK. PML and PML nuclear bodies: implications in antiviral defence. Biochimie. 2007;89:819–30.PubMedCrossRefGoogle Scholar
  40. 40.
    Geoffroy MC, Chelbi-Alix MK. Role of promyelocytic leukemia protein in host antiviral defense. J Interferon Cytokine Res. 2011;31:145–58.PubMedCrossRefGoogle Scholar
  41. 41.
    Dong S, Stenoien DL, Qiu J, Mancini MA, Tweardy DJ. Reduced intranuclear mobility of APL fusion proteins accompanies their mislocalization and results in sequestration and decreased mobility of retinoid X receptor alpha. Mol Cell Biol. 2004;24:4465–75.PubMedCrossRefGoogle Scholar
  42. 42.
    Rivera OJ, Song CS, Centonze VE, Lechleiter JD, Chatterjee B, Roy AK. Role of the promyelocytic leukemia body in the dynamic interaction between the androgen receptor and steroid receptor coactivator-1 in living cells. Mol Endocrinol. 2003;17:128–40.PubMedCrossRefGoogle Scholar
  43. 43.
    Chen YC, Kappel C, Beaudouin J, Eils R, Spector DL. Live cell dynamics of promyelocytic leukemia nuclear bodies upon entry into and exit from mitosis. Mol Biol Cell. 2008;19:3147–62.PubMedCrossRefGoogle Scholar
  44. 44.
    Eskiw CH, Dellaire G, Mymryk JS, Bazett-Jones DP. Size, position and dynamic behavior of PML nuclear bodies following cell stress as a paradigm for supramolecular trafficking and assembly. J Cell Sci. 2003;116:4455–66.PubMedCrossRefGoogle Scholar
  45. 45.
    Short KM, Cox TC. Subclassification of the RBCC/TRIM superfamily reveals a novel motif necessary for microtubule binding. J Biol Chem. 2006;281:8970–80.PubMedCrossRefGoogle Scholar
  46. 46.
    McDonald D, Vodicka MA, Lucero G, Svitkina TM, Borisy GG, Emerman M, et al. Visualization of the intracellular behavior of HIV in living cells. J Cell Biol. 2002;159:441–52.PubMedCrossRefGoogle Scholar
  47. 47.
    Diaz-Griffero F, Gallo DE, Hope TJ, Sodroski J. Trafficking of some old world primate TRIM5alpha proteins through the nucleus. Retrovirology. 2011;8:38.PubMedCrossRefGoogle Scholar
  48. 48.
    Arriagada G, Muntean LN, Goff SP. SUMO-interacting motifs of human TRIM5alpha are important for antiviral activity. PLoS Pathog. 2011;7:e1002019.PubMedCrossRefGoogle Scholar
  49. 49.
    Wu X, Anderson JL, Campbell EM, Joseph AM, Hope TJ. Proteasome inhibitors uncouple rhesus TRIM5alpha restriction of HIV-1 reverse transcription and infection. Proc Natl Acad Sci U S A. 2006;103:7465–70.PubMedCrossRefGoogle Scholar
  50. 50.
    Anderson JL, Campbell EM, Wu X, Vandegraaff N, Engelman A, Hope TJ. Proteasome inhibition reveals that a functional preintegration complex intermediate can be generated during restriction by diverse TRIM5 proteins. J Virol. 2006;80:9754–60.PubMedCrossRefGoogle Scholar
  51. 51.
    Rold CJ, Aiken C. Proteasomal degradation of TRIM5alpha during retrovirus restriction. PLoS Pathog. 2008;4:e1000074.PubMedCrossRefGoogle Scholar
  52. 52.
    O'Connor C, Pertel T, Gray S, Robia SL, Bakowska JC, Luban J, et al. p62/sequestosome-1 associates with and sustains the expression of retroviral restriction factor TRIM5alpha. J Virol. 2010;84:5997–6006.PubMedCrossRefGoogle Scholar
  53. 53.
    Christian F, Anthony DF, Vadrevu S, Riddell T, Day JP, McLeod R, et al. p62 (SQSTM1) and cyclic AMP phosphodiesterase-4A4 (PDE4A4) locate to a novel, reversible protein aggregate with links to autophagy and proteasome degradation pathways. Cell Signal. 2010;22:1576–96.PubMedCrossRefGoogle Scholar
  54. 54.
    Geetha T, Seibenhener ML, Chen L, Madura K, Wooten MW. p62 serves as a shuttling factor for TrkA interaction with the proteasome. Biochem Biophys Res Commun. 2008;374:33–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Seibenhener ML, Babu JR, Geetha T, Wong HC, Krishna NR, Wooten MW. Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol. 2004;24:8055–68.PubMedCrossRefGoogle Scholar
  56. 56.
    Johansen T, Lamark T. Selective autophagy mediated by autophagic adapter proteins. Autophagy. 2011;7:279–96.PubMedCrossRefGoogle Scholar
  57. 57.
    El Bougrini J, Dianoux L, Chelbi-Alix MK. PML positively regulates interferon gamma signaling. Biochimie. 2011;93:389–98.PubMedCrossRefGoogle Scholar
  58. 58.
    Gack MU, Shin YC, Joo CH, Urano T, Liang C, Sun L, et al. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature. 2007;446:916–20.PubMedCrossRefGoogle Scholar
  59. 59.
    Ishii T, Ohnuma K, Murakami A, Takasawa N, Yamochi T, Iwata S, et al. SS-A/Ro52, an autoantigen involved in CD28-mediated IL-2 production. J Immunol. 2003;170:3653–61.PubMedGoogle Scholar
  60. 60.
    Kim JY, Ozato K. The sequestosome 1/p62 attenuates cytokine gene expression in activated macrophages by inhibiting IFN regulatory factor 8 and TNF receptor-associated factor 6/NF-kappaB activity. J Immunol. 2009;182:2131–40.PubMedCrossRefGoogle Scholar
  61. 61.
    Kong HJ, Anderson DE, Lee CH, Jang MK, Tamura T, Tailor P, et al. Cutting edge: autoantigen Ro52 is an interferon inducible E3 ligase that ubiquitinates IRF-8 and enhances cytokine expression in macrophages. J Immunol. 2007;179:26–30.PubMedGoogle Scholar
  62. 62.
    Ryu YS, Lee Y, Lee KW, Hwang CY, Maeng JS, Kim JH, et al. TRIM32 protein sensitizes cells to tumor necrosis factor (TNFalpha)-induced apoptosis via its RING domain-dependent E3 ligase activity against X-linked inhibitor of apoptosis (XIAP). J Biol Chem. 2011;286:25729–38.PubMedCrossRefGoogle Scholar
  63. 63.
    Shi M, Deng W, Bi E, Mao K, Ji Y, Lin G, et al. TRIM30 alpha negatively regulates TLR-mediated NF-kappa B activation by targeting TAB2 and TAB3 for degradation. Nat Immunol. 2008;9:369–77.PubMedCrossRefGoogle Scholar
  64. 64.
    Yu S, Gao B, Duan Z, Xu W, Xiong S. Identification of tripartite motif-containing 22 (TRIM22) as a novel NF-kappaB activator. Biochem Biophys Res Commun. 2011;410:247–51.PubMedCrossRefGoogle Scholar
  65. 65.
    Yamauchi K, Wada K, Tanji K, Tanaka M, Kamitani T. Ubiquitination of E3 ubiquitin ligase TRIM5 alpha and its potential role. FEBS J. 2008;275:1540–55.PubMedCrossRefGoogle Scholar
  66. 66.
    Lienlaf M, Hayashi F, Di Nunzio F, Tochio N, Kigawa T, Yokoyama S, et al. Contribution of E3-Ubiquitin Ligase Activity to HIV-1 Restriction by TRIM5{alpha}rh: Structure of the RING Domain of TRIM5{alpha}. J Virol. 2011;85:8725–37.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Microbiology and Immunology, Stritch School of MedicineLoyola University ChicagoMaywoodUSA

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