HTLV-1 Rex: the courier of viral messages making use of the host vehicle

The human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus causing an aggressive T-cell malignancy, adult T-cell leukemia (ATL). Although HTLV-1 has a compact RNA genome, it has evolved elaborate mechanisms to maximize its coding potential. The structural proteins Gag, Pro, and Pol are encoded in the unspliced form of viral mRNA, whereas the Env protein is encoded in singly spliced viral mRNA. Regulatory and accessory proteins, such as Tax, Rex, p30II, p12, and p13, are translated only from fully spliced mRNA. For effective viral replication, translation from all forms of HTLV-1 transcripts has to be achieved in concert, although unspliced mRNA are extremely unstable in mammalian cells. It has been well recognized that HTLV-1 Rex enhances the stability of unspliced and singly spliced HTLV-1 mRNA by promoting nuclear export and thereby removing them from the splicing site. Rex specifically binds to the highly structured Rex responsive element (RxRE) located at the 3′ end of all HTLV-1 mRNA. Rex then binds to the cellular nuclear exporter, CRM1, via its nuclear export signal domain and the Rex–viral transcript complex is selectively exported from the nucleus to the cytoplasm for effective translation of the viral proteins. Yet, the mechanisms by which Rex inhibits the cellular splicing machinery and utilizes the cellular pathways beneficial to viral survival in the host cell have not been fully explored. Furthermore, physiological impacts of Rex against homeostasis of the host cell via interactions with numerous cellular proteins have been largely left uninvestigated. In this review, we focus on the biological importance of HTLV-1 Rex in the HTLV-1 life cycle by following the historical path in the literature concerning this viral post-transcriptional regulator from its discovery to this day. In addition, for future studies, we discuss recently discovered aspects of HTLV-1 Rex as a post-transcriptional regulator and its use in host cellular pathways.

[1]  T. R. Reddy,et al.  Cellular proteins and HIV-1 Rev function. , 2009, Current HIV research.

[2]  M. Yoshida,et al.  Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Prabhakar R. Gudla,et al.  Human T-cell leukemia virus type 1 p8 protein increases cellular conduits and virus transmission , 2010, Proceedings of the National Academy of Sciences.

[4]  K. Jeang,et al.  Human T-cell leukemia virus type 1 (HTLV-1) and leukemic transformation: viral infectivity, Tax, HBZ and therapy , 2011, Oncogene.

[5]  C. Nicot,et al.  Human T-lymphotropic type 1 virus p30 inhibits homologous recombination and favors unfaithful DNA repair. , 2011, Blood.

[6]  I. Chen,et al.  Regulation of HTLV-II gene expression by Rex involves positive and negative cis-acting elements in the 5'long terminal repeat. , 1991, Virology.

[7]  M. Reitz,et al.  Expression of alternatively spliced human T-lymphotropic virus type I pX mRNA in infected cell lines and in primary uncultured cells from patients with adult T-cell leukemia/lymphoma and healthy carriers. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[8]  O. Marin,et al.  Effects of human T-cell leukemia virus type 1 (HTLV-1) p13 on mitochondrial K+ permeability: A new member of the viroporin family? , 2010, FEBS Letters.

[9]  M. Malim,et al.  Structure-function analyses of the HTLV-I Rex and HIV-1 Rev RNA response elements: insights into the mechanism of Rex and Rev action. , 1990, Genes & development.

[10]  T. Misteli,et al.  HTLV-1-encoded p30II is a post-transcriptional negative regulator of viral replication , 2004, Nature Medicine.

[11]  Norman E. Davey,et al.  Attributes of short linear motifs. , 2012, Molecular bioSystems.

[12]  Lianbo Yu,et al.  Kinetic Analysis of Human T-Cell Leukemia Virus Type 1 Gene Expression in Cell Culture and Infected Animals , 2009, Journal of Virology.

[13]  P. Vogt.  Human T-Cell Leukemia Virus , 1985, Current Topics in Microbiology and Immunology.

[14]  P. Pinton,et al.  The p13 protein of human T cell leukemia virus type 1 (HTLV-1) modulates mitochondrial membrane potential and calcium uptake. , 2010, Biochimica et biophysica acta.

[15]  A. Israël,et al.  Altered Expression of Tyrosine Kinases of the Src and Syk Families in Human T-Cell Leukemia Virus Type 1-Infected T-Cell Lines , 1999, Journal of Virology.

[16]  Jay Vyas,et al.  Viral infection and human disease--insights from minimotifs. , 2008, Frontiers in bioscience : a journal and virtual library.

[17]  A. Barabasi,et al.  An empirical framework for binary interactome mapping , 2008, Nature Methods.

[18]  Jun-ichirou Yasunaga,et al.  HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Claudio Cobelli,et al.  Pacific Symposium on Biocomputing 15:421-432(2010) RETROVIRUS HTLV-1 GENE CIRCUIT: A POTENTIAL OSCILLATOR FOR EUKARYOTES , 2022 .

[20]  G. Pavlakis,et al.  Different sites of interaction for Rev, Tev, and Rex proteins within the Rev-responsive element of human immunodeficiency virus type 1 , 1990, Journal of virology.

[21]  J. Darlix,et al.  Translational control of retroviruses , 2007, Nature Reviews Microbiology.

[22]  M. Lairmore,et al.  Human T-Cell Leukemia Virus Type 2 Rex Carboxy Terminus Is an Inhibitory/Stability Domain That Regulates Rex Functional Activity and Viral Replication , 2009, Journal of Virology.

[23]  W C Greene,et al.  Comparative analysis of the HTLV-I Rex and HIV-1 Rev trans-regulatory proteins and their RNA response elements. , 1989, Genes & development.

[24]  Y. Hakata,et al.  Rat CRM1 Is Responsible for the Poor Activity of Human T-Cell Leukemia Virus Type 1 Rex Protein in Rat Cells , 2001, Journal of Virology.

[25]  Norman E. Davey,et al.  How viruses hijack cell regulation. , 2011, Trends in biochemical sciences.

[26]  E. Kress,et al.  Critical role of hnRNP A1 in HTLV-1 replication in human transformed T lymphocytes , 2005, Retrovirology.

[27]  L. Ratner,et al.  The HTLV-1 hbz antisense gene indirectly promotes tax expression via down-regulation of p30(II) mRNA. , 2011, Virology.

[28]  S. Matsushita,et al.  Involvement of Human CRM1 (Exportin 1) in the Export and Multimerization of the Rex Protein of Human T-Cell Leukemia Virus Type 1 , 1998, Journal of Virology.

[29]  T. Honjo,et al.  The nucleolar localisation signal of the HTLV-I protein p27rex is important for stabilisation of IL-2 receptor alpha subunit mRNA by p27rex. , 1991, Biochemical and biophysical research communications.

[30]  A. Dejean,et al.  SUMO: of branched proteins and nuclear bodies , 2001, Oncogene.

[31]  Johnm . Taylor,et al.  HTLV-1 and apoptosis: role in cellular transformation and recent advances in therapeutic approaches , 2008, Apoptosis.

[32]  M. Malim,et al.  Importin β Can Mediate the Nuclear Import of an Arginine-Rich Nuclear Localization Signal in the Absence of Importin α , 1999, Molecular and Cellular Biology.

[33]  M. Malim,et al.  Immunodeficiency virus rev trans-activator modulates the expression of the viral regulatory genes , 1988, Nature.

[34]  G. Franchini,et al.  Molecular biology and pathogenesis of the human T‐cell leukaemia/lymphotropic virus Type‐1 (HTLV‐1) , 2001, International journal of experimental pathology.

[35]  S. L. Wong,et al.  Towards a proteome-scale map of the human protein–protein interaction network , 2005, Nature.

[36]  L. Chieco‐Bianchi,et al.  Inhibition of human T-cell leukemia virus type 2 Rex function by truncated forms of Rex encoded in alternatively spliced mRNAs , 1997, Journal of virology.

[37]  M. Dundr,et al.  Human T-cell Leukemia Virus Type I p30 Nuclear/Nucleolar Retention Is Mediated through Interactions with RNA and a Constituent of the 60 S Ribosomal Subunit* , 2006, Journal of Biological Chemistry.

[38]  M. Ward,et al.  Phosphorylation regulates human T-cell leukemia virus type 1 Rex function , 2009, Retrovirology.

[39]  M. Salemi,et al.  The simian origins of the pathogenic human T-cell lymphotropic virus type I. , 1998, Trends in microbiology.

[40]  P. Lichter,et al.  Nucleocytoplasmic transport of HTLV-1 RNA is regulated by two independent LTR encoded nuclear retention elements , 1998, Oncogene.

[41]  M. Seiki,et al.  The second pX product p27 x‐III of HTLV‐1 is required for gag gene expression , 1986, FEBS letters.

[42]  M. Ward,et al.  Site-Specific Phosphorylation Regulates Human T-Cell Leukemia Virus Type 2 Rex Function In Vivo , 2009, Journal of Virology.

[43]  P. Green,et al.  Human T lymphotropic virus type 1 regulatory and accessory gene transcript expression and export are not rex dependent. , 2012, AIDS research and human retroviruses.

[44]  J. Kjems,et al.  In Vitro Interaction between Human Immunodeficiency Virus Type 1 Rev Protein and Splicing Factor ASF/SF2-associated Protein, p32 (*) , 1996, The Journal of Biological Chemistry.

[45]  C. Pise-Masison,et al.  Suppression of HTLV-1 replication by Tax-mediated rerouting of the p13 viral protein to nuclear speckles. , 2011, Blood.

[46]  H. Casse,et al.  The human T-cell leukemia virus type 1 Rex regulatory protein exhibits an impaired functionality in human lymphoblastoid Jurkat T cells , 1997, Journal of virology.

[47]  Joseph R. Nevins,et al.  The HTLV-I rex response element mediates a novel form of mRNA polyadenylation , 1991, Cell.

[48]  Juliette Martin,et al.  Heterogeneous Nuclear Ribonucleoprotein A1 Interferes with the Binding of the Human T Cell Leukemia Virus Type 1 Rex Regulatory Protein to Its Response Element* , 2002, The Journal of Biological Chemistry.

[49]  M. Yoshida,et al.  p27x-III and p21x-III, proteins encoded by the pX sequence of human T-cell leukemia virus type I. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[50]  H. Igarashi,et al.  Presence of antibodies to p21X and/or p27rex proteins in sera from human T-cell leukemia virus type I-infected individuals. , 1996, Journal of virological methods.

[51]  T. Maniatis,et al.  HIV Rev-dependent binding of SF2/ASF to the Rev response element: possible role in Rev-mediated inhibition of HIV RNA splicing. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[52]  P. Bahadoran,et al.  Hypoxia and MITF control metastatic behaviour in mouse and human melanoma cells , 2012, Oncogene.

[53]  Chou-Wei Chang,et al.  Epstein-Barr Virus Protein Kinase BGLF4 Targets the Nucleus through Interaction with Nucleoporins , 2012, Journal of Virology.

[54]  M. Bellon,et al.  HTLV-1 Yin and Yang: Rex and p30 master regulators of viral mRNA trafficking. , 2008, AIDS reviews.

[55]  M. Reitz,et al.  Isolation of a new type C retrovirus (HTLV) in primary uncultured cells of a patient with Sézary T-cell leukaemia , 1981, Nature.

[56]  C. Pise-Masison,et al.  Hijacking the T-cell communication network by the human T-cell leukemia/lymphoma virus type 1 (HTLV-1) p12 and p8 proteins. , 2010, Molecular aspects of medicine.

[57]  Aftab J. Ahmed,et al.  Phosphorylation of the Rex protein of human T-cell leukemia virus type I. , 1992, The Journal of biological chemistry.

[58]  M. Malim,et al.  The HIV-1 Rev protein. , 1998, Annual review of microbiology.

[59]  Mitsuaki,et al.  Post‐transcriptional regulator (rex) of HTLV‐1 initiates expression of viral structural proteins but suppresses expression of regulatory proteins. , 1988, The EMBO journal.

[60]  Yingfeng Zheng,et al.  Contribution of Host Nucleoporin 62 in HIV-1 Integrase Chromatin Association and Viral DNA Integration* , 2012, The Journal of Biological Chemistry.

[61]  H. Nishitsuji,et al.  Interaction of human T‐cell lymphotropic virus type I Rex protein with Dicer suppresses RNAi silencing , 2010, FEBS letters.

[62]  M. Bellon,et al.  Nuclear Export and Expression of Human T-Cell Leukemia Virus Type 1 tax/rex mRNA Are RxRE/Rex Dependent , 2012, Journal of Virology.

[63]  Bryan R. Cullen,et al.  The Arginine-Rich Domains Present in Human Immunodeficiency Virus Type 1 Tat and Rev Function as Direct Importin β-Dependent Nuclear Localization Signals , 1999, Molecular and Cellular Biology.

[64]  M. Gröne,et al.  The HTLV-1 Rex protein induces nuclear accumulation of unspliced viral RNA by avoiding intron excision and degradation. , 1996, Virology.

[65]  M. Yoshida,et al.  Transcriptional (p40x) and post-transcriptional (p27x-III) regulators are required for the expression and replication of human T-cell leukemia virus type I genes. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[66]  M. Cole,et al.  A Human T-Cell Lymphotropic Virus Type 1 Enhancer of Myc Transforming Potential Stabilizes Myc-TIP60 Transcriptional Interactions , 2005, Molecular and Cellular Biology.

[67]  Joshua Arnold,et al.  Enhancement of infectivity and persistence in vivo by HBZ, a natural antisense coded protein of HTLV-1. , 2006, Blood.

[68]  T. Honjo,et al.  HTLV‐1 p27rex stabilizes human interleukin‐2 receptor alpha chain mRNA. , 1990, The EMBO journal.

[69]  R. Gallo.  The discovery of the first human retrovirus: HTLV-1 and HTLV-2 , 2005, Retrovirology.

[70]  Megha K. Purohit,et al.  Air1 Zinc Knuckles 4 and 5 and a Conserved IWRXY Motif Are Critical for the Function and Integrity of the Trf4/5-Air1/2-Mtr4 Polyadenylation (TRAMP) RNA Quality Control Complex* , 2011, The Journal of Biological Chemistry.

[71]  H. Hara,et al.  Human T-Lymphotropic Virus , 2013, Neuroviral Infections.

[72]  M. Yoshida,et al.  Human adult T-cell leukemia virus: complete nucleotide sequence of the provirus genome integrated in leukemia cell DNA. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[73]  M. Boxus,et al.  The HTLV-1 Tax interactome , 2008, Retrovirology.

[74]  Kuan-Teh Jeang,et al.  Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation , 2007, Nature Reviews Cancer.

[75]  K. Takatsuki,et al.  Discovery of adult T-cell leukemia , 2005, Retrovirology.

[76]  F. Kashanchi,et al.  Transcriptional and post-transcriptional gene regulation of HTLV-1 , 2005, Oncogene.

[77]  I. Koralnik,et al.  The p12I, p13II, and p30II proteins encoded by human T-cell leukemia/lymphotropic virus type I open reading frames I and II are localized in three different cellular compartments , 1993, Journal of virology.

[78]  T. Hope,et al.  Oligomerization and RNA binding domains of the type 1 human immunodeficiency virus Rev protein: a dual function for an arginine-rich binding motif. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[79]  L. Ratner,et al.  Histone acetyltransferase (HAT) activity of p300 modulates human T lymphotropic virus type 1 p30II-mediated repression of LTR transcriptional activity. , 2006, Virology.

[80]  D. Mann,et al.  Isolation and transmission of human retrovirus (human t-cell leukemia virus). , 1983, Science.

[81]  John D. Minna,et al.  Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma , 1980, Proceedings of the National Academy of Sciences.

[82]  T. Dobner,et al.  Human Pathogens and the Host Cell SUMOylation System , 2011, Journal of Virology.

[83]  J. Grainger.  The Virus , 1940, Nature.

[84]  D. Olive,et al.  Altered splicing in hematological malignancies reveals a tissue-specific translational block of the Src-family tyrosine kinase fyn brain isoform expression , 2004, Leukemia.

[85]  P. Green,et al.  The human T-cell leukemia virus Rex protein. , 2005, Frontiers in bioscience : a journal and virtual library.

[86]  M. Reitz,et al.  The virus of Japanese adult T-cell leukaemia is a member of the human T-cell leukaemia virus group , 1982, Nature.

[87]  E. C. Schirmer,et al.  Herpes Simplex Virus ICP27 Protein Directly Interacts with the Nuclear Pore Complex through Nup62, Inhibiting Host Nucleocytoplasmic Transport Pathways , 2012, The Journal of Biological Chemistry.

[88]  M. Malim,et al.  Functional replacement of the HIV-1 rev protein by the HTLV-1 rex protein , 1988, Nature.

[89]  C. Nicot,et al.  Human T-cell Lymphotrophic Virus Type I Rex and p30 Interactions Govern the Switch between Virus Latency and Replication* , 2007, Journal of Biological Chemistry.

[90]  T. Nosaka,et al.  Protein kinase inhibitor H-7 blocks accumulation of unspliced mRNA of human T-cell leukemia virus type I (HTLV-I). , 1990, Biochemical and biophysical research communications.

[91]  Jaclyn R. Gareau,et al.  The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition , 2010, Nature Reviews Molecular Cell Biology.

[92]  F. Melchior,et al.  SUMO: regulating the regulator , 2006, Cell Division.

[93]  A. Krainer,et al.  Functional expression of cloned human splicing factor SF2: homology to rna-binding proteins, U1 70K, and drosophila splicing regulators , 1991, Cell.

[94]  H. Zoghbi,et al.  SUMOylation of the Polyglutamine Repeat Protein, Ataxin-1, Is Dependent on a Functional Nuclear Localization Signal* , 2005, Journal of Biological Chemistry.

[95]  P. Green,et al.  Comparative biology of human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2 , 2005, Oncogene.

[96]  T. Kodama,et al.  Stabilization of interleukin-2 receptor alpha chain mRNA by HTLV-1 Rex in mouse L cells: lower amounts of Rex do not stabilize the mRNA. , 1994, Biochemical and Biophysical Research Communications - BBRC.

[97]  M. Romanelli,et al.  Comparison of the Genetic Organization, Expression Strategies and Oncogenic Potential of HTLV-1 and HTLV-2 , 2011, Leukemia research and treatment.

[98]  A. Corradin,et al.  Kinetics and intracellular compartmentalization of HTLV-1 gene expression: nuclear retention of HBZ mRNAs. , 2011, Blood.

[99]  刘金明,et al.  IL-13受体α2降低血吸虫病肉芽肿的炎症反应并延长宿主存活时间[英]/Mentink-Kane MM,Cheever AW，Thompson RW，et al//Proc Natl Acad Sci U S A , 2005 .

[100]  S. Hughes,et al.  Roles of viral and cellular proteins in the expression of alternatively spliced HTLV-1 pX mRNAs. , 2003, Virology.

[101]  V. Andresen,et al.  HTLV-1 p13, a small protein with a busy agenda. , 2010, Molecular aspects of medicine.

[102]  M. Yoshida,et al.  The U5 sequence is a cis-acting repressive element for genomic RNA expression of human T cell leukemia virus type I. , 1990, Virology.

[103]  Y. Yoneda,et al.  Nucleocytoplasmic protein traffic and its significance to cell function , 2000, Genes to cells : devoted to molecular & cellular mechanisms.

[104]  Robert Giegerich,et al.  KnotInFrame: prediction of −1 ribosomal frameshift events , 2008, Nucleic acids research.

[105]  K. Ohshima,et al.  HTLV-1 bZIP Factor Induces T-Cell Lymphoma and Systemic Inflammation In Vivo , 2011, PLoS pathogens.

[106]  C. Nicot,et al.  HTLV-I p30: a versatile protein modulating virus replication and pathogenesis. , 2010, Molecular aspects of medicine.

[107]  R. Anupam,et al.  Human T-lymphotropic Virus Type 1 p30 Interacts with REGγ and Modulates ATM (Ataxia Telangiectasia Mutated) to Promote Cell Survival* , 2011, The Journal of Biological Chemistry.

[108]  J. Karn,et al.  Flexible regions of RNA structure facilitate co-operative Rev assembly on the Rev-response element. , 1996, Journal of molecular biology.

[109]  A. Mouland,et al.  HIV-1 remodels the nuclear pore complex , 2011, The Journal of cell biology.

[110]  J W DUGGAN,et al.  Herpes simplex virus. , 1961, Transactions of the Canadian Ophthalmological Society.

[111]  P. Green,et al.  Human T Lymphotropic Virus Type 1 (HTLV-1): Molecular Biology and Oncogenesis , 2010, Viruses.

[112]  C. Nicot,et al.  Human T-cell leukemia/lymphoma virus type 1 nonstructural genes and their functions , 2005, Oncogene.

[113]  Sozanne R. Solmaz,et al.  Molecular Architecture of the Transport Channel of the Nuclear Pore Complex , 2011, Cell.

[114]  K. Araki,et al.  Human T cell leukaemia virus type 1 p21X mRNA: constitutive expression in peripheral blood mononuclear cells of patients with adult T cell leukaemia. , 1992, The Journal of general virology.

[115]  R. Fukumoto,et al.  T-Cell Control by Human T-Cell Leukemia/Lymphoma Virus Type 1 , 2003, International journal of hematology.

[116]  T. Copeland,et al.  Nucleolar targeting signal of Rex protein of human T-cell leukemia virus type I specifically binds to nucleolar shuttle protein B-23. , 1993, The Journal of biological chemistry.