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Cited by 47T-cell and Retrovirus StudiesHIV Research and TreatmentProtein Kinase Regulation and GTPase Signaling

Gem-Induced Cytoskeleton Remodeling Increases Cellular Migration of HTLV-1-Infected Cells, Formation of Infected-to-Target T-Cell Conjugates and Viral Transmission

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Chevalier, Sébastien A., Turpin, Jocelyn, Cachat, Anne, Afonso, Philippe V., Gessain, Antoine, Brady, John N., Pise-Masison, Cynthia A., Mahieux, Renaud·2014·PLoS Pathogens
DOI 10.1371/journal.ppat.1003917PMC PMC3937318
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Abstract

Efficient HTLV-1 viral transmission occurs through cell-to-cell contacts. The Tax viral transcriptional activator protein facilitates this process. Using a comparative transcriptomic analysis, we recently identified a series of genes up-regulated in HTLV-1 Tax expressing T-lymphocytes. We focused our attention towards genes that are important for cytoskeleton dynamic and thus may possibly modulate cell-to-cell contacts. We first demonstrate that Gem, a member of the small GTP-binding proteins within the Ras superfamily, is expressed both at the RNA and protein levels in Tax-expressing cells and in HTLV-1-infected cell lines. Using a series of ChIP assays, we show that Tax recruits CREB and CREB Binding Protein (CBP) onto a c-AMP Responsive Element (CRE) present in the gem promoter. This CRE sequence is required to drive Tax-activated gem transcription. Since Gem is involved in cytoskeleton remodeling, we investigated its role in infected cells motility. We show that Gem co-localizes with F-actin and is involved both in T-cell spontaneous cell migration as well as chemotaxis in the presence of SDF-1/CXCL12. Importantly, gem knock-down in HTLV-1-infected cells decreases cell migration and conjugate formation. Finally, we demonstrate that Gem plays an important role in cell-to-cell viral transmission.

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  • HTLV-1 Tax acts synergistically with ICAM-1, activating CREB signaling, which increases expression of the GTP-binding protein Gem.

    “The viral accessory protein, Tax, acts synergistically with ICAM-1, activating the CREB signaling pathway. This activation increases the expression of the GTP-binding protein Gem, which regulates cytoskeleton reorganization and cell migration [42].”

    From HIV-1 and HTLV-1 Transmission Modes: Mechanisms and Importance for Virus Spread (2022) · cites this paper as [42]

    The Results section, “Tax recruits CREB and CBP onto the Gem promoter” (page unavailable), shows that Tax acts with CREB and CBP at the gem promoter to increase transcription. The Results section on Gem expression also reports increased Gem RNA and protein after Tax expression. Our copy does not support the attributed synergy with ICAM-1; a search for ICAM-1 found no relevant passage. (LLM, conf=0.88)

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Research works printed but not linked: 47

  1. [1]Gessain A, Cassar O (2012) Epidemiological Aspects and World Distribution of HTLV-1 Infection. Front Microbiol 3: 388. 23162541 PMC3498738
  2. [2]Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H (1977) Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood 50: 481– 492. 301762
  3. [3]Gessain A, Barin F, Vernant JC, Gout O, Maurs L, et al (1985) Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet 2: 407– 410. 2863442
  4. [4]Osame M, Usuku K, Izumo S, Ijichi N, Amitani H, et al (1986) HTLV-I associated myelopathy, a new clinical entity. Lancet 1: 1031– 1032. 2871307
  5. [5]Boxus M, Willems L (2009) Mechanisms of HTLV-1 persistence and transformation. Br J Cancer 101: 1497– 1501. 19861996 PMC2778510
  6. [6]Currer R, Van Duyne R, Jaworski E, Guendel I, Sampey G, et al (2012) HTLV tax: a fascinating multifunctional co-regulator of viral and cellular pathways. Front Microbiol 3: 406. 23226145 PMC3510432
  7. [7]Journo C, Douceron E, Mahieux R (2009) HTLV gene regulation: because size matters, transcription is not enough. Future Microbiol 4: 425– 440. 19416012
  8. [8]Bellon M, Baydoun HH, Yao Y, Nicot C (2010) HTLV-I Tax-dependent and -independent events associated with immortalization of human primary T lymphocytes. Blood 115: 2441– 2448. 20093405 PMC2845900
  9. [9]Hasegawa H, Sawa H, Lewis MJ, Orba Y, Sheehy N, et al (2006) Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I. Nat Med 12: 466– 472. 16550188
  10. [11]Pique C, Jones KS (2012) Pathways of cell-cell transmission of HTLV-1. Front Microbiol 3: 378. 23109932 PMC3479854
  11. [12]Igakura T, Stinchcombe JC, Goon PK, Taylor GP, Weber JN, et al (2003) Spread of HTLV-I between lymphocytes by virus-induced polarization of the cytoskeleton. Science 299: 1713– 1716. 12589003
  12. [13]Pais-Correia AM, Sachse M, Guadagnini S, Robbiati V, Lasserre R, et al (2010) Biofilm-like extracellular viral assemblies mediate HTLV-1 cell-to-cell transmission at virological synapses. Nat Med 16: 83– 89. 20023636
  13. [14]Nejmeddine M, Barnard AL, Tanaka Y, Taylor GP, Bangham CR (2005) Human T-lymphotropic virus, type 1, tax protein triggers microtubule reorientation in the virological synapse. J Biol Chem 280: 29653– 29660. 15975923
  14. [15]Nejmeddine M, Negi VS, Mukherjee S, Tanaka Y, Orth K, et al (2009) HTLV-1-Tax and ICAM-1 act on T-cell signal pathways to polarize the microtubule-organizing center at the virological synapse. Blood 114: 1016– 1025. 19494354
  15. [16]Majorovits E, Nejmeddine M, Tanaka Y, Taylor GP, Fuller SD, et al (2008) Human T-lymphotropic virus-1 visualized at the virological synapse by electron tomography. PLoS One 3: e2251. 18509526 PMC2386264
  16. [17]Chevalier SA, Durand S, Dasgupta A, Radonovich M, Cimarelli A, et al (2012) The transcription profile of Tax-3 is more similar to Tax-1 than Tax-2: insights into HTLV-3 potential leukemogenic properties. PLoS One 7: e41003. 22911729 PMC3401231
  17. [18]Ward Y, Kelly K (2006) Gem protein signaling and regulation. Methods Enzymol 407: 468– 483. 16757346
  18. [19]Kelly K (2005) The RGK family: a regulatory tail of small GTP-binding proteins. Trends Cell Biol 15: 640– 643. 16242932
  19. [20]Opatowsky Y, Sasson Y, Shaked I, Ward Y, Chomsky-Hecht O, et al (2006) Structure-function studies of the G-domain from human gem, a novel small G-protein. FEBS Lett 580: 5959– 5964. 17052716 PMC1934412
  20. [21]Correll RN, Pang C, Niedowicz DM, Finlin BS, Andres DA (2008) The RGK family of GTP-binding proteins: regulators of voltage-dependent calcium channels and cytoskeleton remodeling. Cell Signal 20: 292– 300. 18042346 PMC2254326
  21. [22]Maguire J, Santoro T, Jensen P, Siebenlist U, Yewdell J, et al (1994) Gem: an induced, immediate early protein belonging to the Ras family. Science 265: 241– 244. 7912851
  22. [23]Hatzoglou A, Ader I, Splingard A, Flanders J, Saade E, et al (2007) Gem associates with Ezrin and acts via the Rho-GAP protein Gmip to down-regulate the Rho pathway. Mol Biol Cell 18: 1242– 1252. 17267693 PMC1839077
  23. [24]Suyama E, Kawasaki H, Nakajima M, Taira K (2003) Identification of genes involved in cell invasion by using a library of randomized hybrid ribozymes. Proc Natl Acad Sci U S A 100: 5616– 5621. 12719525 PMC156250
  24. [25]Kress AK, Kalmer M, Rowan AG, Grassmann R, Fleckenstein B (2011) The tumor marker Fascin is strongly induced by the Tax oncoprotein of HTLV-1 through NF-kappaB signals. Blood 117: 3609– 3612. 21300980
  25. [26]Ng PW, Iha H, Iwanaga Y, Bittner M, Chen Y, et al (2001) Genome-wide expression changes induced by HTLV-1 Tax: evidence for MLK-3 mixed lineage kinase involvement in Tax-mediated NF-kappaB activation. Oncogene 20: 4484– 4496. 11494144
  26. [27]Pise-Masison CA, Radonovich M, Mahieux R, Chatterjee P, Whiteford C, et al (2002) Transcription profile of cells infected with human T-cell leukemia virus type I compared with activated lymphocytes. Cancer Res 62: 3562– 3571. 12068005
  27. [28]Conkright MD, Guzman E, Flechner L, Su AI, Hogenesch JB, et al (2003) Genome-wide analysis of CREB target genes reveals a core promoter requirement for cAMP responsiveness. Mol Cell 11: 1101– 1108. 12718894
  28. [29]Kwok RP, Laurance ME, Lundblad JR, Goldman PS, Shih H, et al (1996) Control of cAMP-regulated enhancers by the viral transactivator Tax through CREB and the co-activator CBP. Nature 380: 642– 646. 8602268
  29. [30]Ward Y, Yap SF, Ravichandran V, Matsumura F, Ito M, et al (2002) The GTP binding proteins Gem and Rad are negative regulators of the Rho-Rho kinase pathway. J Cell Biol 157: 291– 302. 11956230 PMC2199248
  30. [31]Mitchison TJ, Cramer LP (1996) Actin-based cell motility and cell locomotion. Cell 84: 371– 379. 8608590
  31. [32]Varrin-Doyer M, Nicolle A, Marignier R, Cavagna S, Benetollo C, et al (2012) Human T lymphotropic virus type 1 increases T lymphocyte migration by recruiting the cytoskeleton organizer CRMP2. J Immunol 188: 1222– 1233. 22227566
  32. [33]Afonso PV, Ozden S, Prevost MC, Schmitt C, Seilhean D, et al (2007) Human blood-brain barrier disruption by retroviral-infected lymphocytes: role of myosin light chain kinase in endothelial tight-junction disorganization. J Immunol 179: 2576– 2583. 17675520
  33. [34]Van Prooyen N, Gold H, Andresen V, Schwartz O, Jones K, et al (2010) Human T-cell leukemia virus type 1 p8 protein increases cellular conduits and virus transmission. Proc Natl Acad Sci U S A 107: 20738– 20743. 21076035 PMC2996430
  34. [35]Riento K, Ridley AJ (2003) Rocks: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol 4: 446– 456. 12778124
  35. [36]Wu Y, Yoder A, Yu D, Wang W, Liu J, et al (2008) Cofilin activation in peripheral CD4 T cells of HIV-1 infected patients: a pilot study. Retrovirology 5: 95. 18928553 PMC2576353
  36. [37]Yoder A, Yu D, Dong L, Iyer SR, Xu X, et al (2008) HIV envelope-CXCR4 signaling activates cofilin to overcome cortical actin restriction in resting CD4 T cells. Cell 134: 782– 792. 18775311 PMC2559857
  37. [38]Arimura N, Inagaki N, Chihara K, Menager C, Nakamura N, et al (2000) Phosphorylation of collapsin response mediator protein-2 by Rho-kinase. Evidence for two separate signaling pathways for growth cone collapse. J Biol Chem 275: 23973– 23980. 10818093
  38. [39]Jayo A, Parsons M, Adams JC (2012) A novel Rho-dependent pathway that drives interaction of fascin-1 with p-Lin-11/Isl-1/Mec-3 kinase (LIMK) 1/2 to promote fascin-1/actin binding and filopodia stability. BMC Biol 10: 72. 22883572 PMC3488970
  39. [40]Li Q, Lu F, Wang K (2012) Modeling of HIV-1 infection: insights to the role of monocytes/macrophages, latently infected T4 cells, and HAART regimes. PLoS One 7: e46026. 23049927 PMC3458829
  40. [41]Nagata K, Ohtani K, Nakamura M, Sugamura K (1989) Activation of endogenous c-fos proto-oncogene expression by human T-cell leukemia virus type I-encoded p40tax protein in the human T-cell line, Jurkat. J Virol 63: 3220– 3226. 2501514 PMC250891
  41. [42]Ward Y, Spinelli B, Quon MJ, Chen H, Ikeda SR, et al (2004) Phosphorylation of critical serine residues in Gem separates cytoskeletal reorganization from down-regulation of calcium channel activity. Mol Cell Biol 24: 651– 661. 14701738 PMC343818
  42. [43]Meertens L, Chevalier S, Weil R, Gessain A, Mahieux R (2004) A 10-amino acid domain within human T-cell leukemia virus type 1 and type 2 tax protein sequences is responsible for their divergent subcellular distribution. J Biol Chem 279: 43307– 43320. 15269214
  43. [44]Cho SJ, Lee SS, Kim YJ, Park BD, Choi JS, et al (2010) Xylocydine, a novel Cdk inhibitor, is an effective inducer of apoptosis in hepatocellular carcinoma cells in vitro and in vivo. Cancer Lett 287: 196– 206. 19616371
  44. [45]Zhou M, Lu H, Park H, Wilson-Chiru J, Linton R, et al (2006) Tax interacts with P-TEFb in a novel manner to stimulate human T-lymphotropic virus type 1 transcription. J Virol 80: 4781– 4791. 16641271 PMC1472077
  45. [46]Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, et al (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9: 676– 682. 22743772 PMC3855844
  46. [47]Journo C, Bonnet A, Favre-Bonvin A, Turpin J, Vinera J, et al (2013) Human T cell leukemia virus type 2 tax-mediated NF-kappaB activation involves a mechanism independent of Tax conjugation to ubiquitin and SUMO. J Virol 87: 1123– 1136. 23135727 PMC3554075
  47. [48]Astier-Gin T, Portail JP, Lafond F, Guillemain B (1995) Identification of HTLV-I- or HTLV-II-producing cells by cocultivation with BHK-21 cells stably transfected with a LTR-lacZ gene construct. J Virol Methods 51: 19– 29. 7730434

Cited by

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Authors
Chevalier, S. A., Turpin, J., Cachat, A., Afonso, P. V., Gessain, A., Brady, J. N., Pise-Masison, C. A., & Mahieux, R.
Affiliations
  • Lyon 1 Université (FR)
  • Centre National de la Recherche Scientifique (FR)
  • National Institutes of Health (US)
Corresponding author
Mahieux, Renaud
ORCID
Venue
PLoS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2014-02-27
Volume
10
Issue
2
Pages
e1003917
ISSN
  • 1553-7366 (ISSN-L)
  • 1553-7374
DOI
10.1371/journal.ppat.1003917
PMC
PMC3937318
OpenAlex
W2047904179
Cited by
47
References
1
Citations by year
2026: 2 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 5 · 2018: 2 · 2017: 8 · 2016: 6 · 2015: 5 · 2014: 4
FWCI
3.50
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Pathogens (publishedVersion, public-domain)
  • Europe PMC (PubMed Central) (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • Spiral (Imperial College London) (submittedVersion, other-oa)
Funders
  • Fondation ARC pour la Recherche sur le Cancer
  • Ligue Contre le Cancer
  • Institut National Du Cancer
  • Servier
  • National Institutes of Health
  • National Cancer Institute
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
HTLV-1, taxation, gems, cytoskeletal remodeling, cell migration, chemotaxis, SDF-1/CXCL12, CREB, CREB-binding protein, F-actin, small GTPases, viral transcriptional activator
MeSH terms
Cell Line, Chemotaxis, Leukocyte, Cytoskeleton, Fluorescent Antibody Technique, T-Lymphocytes, Transduction, Genetic, Immunoblotting, Human T-lymphotropic virus 1, Transcriptional Activation, Gene Expression Regulation, Viral, Gene Products, tax, Reverse Transcriptase Polymerase Chain Reaction, Monomeric GTP-Binding Proteins, Chromatin Immunoprecipitation

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