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Transactivation of the novel 5’ cis-acting element of mouse mammary tumor virus (MMTV) by human retroviral transactivators Tat and Tax

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Khader, Thanumol Abdul, Ahmad, Waqar, Akhlaq, Shaima, Panicker, Neena Gopinathan, Gull, Bushra, Baby, Jasmin, Rizvi, Tahir A., Mustafa, Farah·2024·Communications Biology
DOI 10.1038/s42003-024-07139-9PMC PMC11569226
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Abstract

The mouse mammary tumor virus (MMTV) encodes a 5’ element crucial for transcription of its genome along with the Rem/Rem-responsive element (RmRE) responsible for nuclear export of this unspliced RNA. Whether the 5’ element is Rem-responsive or has any functional interaction with host/viral factors to facilitate MMTV gene expression was tested in this study. Our results reveal that the 5’ element is non-responsive to Rem, but can be transactivated by both HIV Tat and HTLV-1 Tax activators. Reciprocally, MMTV could transactivate not only HIV TAR (similar to HTLV Tax), but also its 5’ element. Furthermore, we reveal involvement of pTEFb, a general elongation factor associated with transactivation by Tat/Tax. This makes MMTV the first betaretrovirus to encode both Rem/RRE and Tat/TAR-Tax/TRE-like transcription regulatory systems. This study should enhance not only our understanding of retrovirus replication and virally-induced cancers/immunodeficiency syndromes, but also development of improved retroviral vectors for human gene therapy. The mouse mammary tumor virus (MMTV) encodes a gene transactivation system similar to HIV Tat/TAR-HTLV Tax/TRE that requires a yet-to-be identified virally-encoded factor and the cellular factor pTEF-b for function.

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  1. [1]Ross, S. R. Mouse mammary tumor virus molecular biology and oncogenesis. Viruses 2, 2000–2012 (2010). 21274409 PMC3026287 · DOI
  2. [2]Dudley, J. P., Golovkina, T. V. & Ross, S. R. Lessons learned from mouse mammary tumor virus in animal models. ILAR J. 57, 12–23 (2016). 27034391 PMC5007637 · DOI
  3. [4]Indik, S., Günzburg, W. H., Salmons, B. & Rouault, F. A novel, mouse mammary tumor virus encoded protein with Rev-like properties. Virology 337, 1–6 (2005). 15914215 · DOI · Paper page
  4. [5]Konstantoulas, C. J. & Indik, S. Mouse mammary tumor virus-based vector transduces non-dividing cells, enters the nucleus via a TNPO3-independent pathway and integrates in a less biased fashion than other retroviruses. Retrovirology 11, 34 (2014). 24779422 PMC4098793 · DOI
  5. [7]Chameettachal, A., Mustafa, F. & Rizvi, T. A. Understanding Retroviral Life Cycle and its Genomic RNA Packaging. J. Mol. Biol. 435, 167924 (2023). 36535429 · DOI · Paper page
  6. [8]Ramdas, P., Sahu, A. K., Mishra, T., Bhardwaj, V. & Chande, A. From Entry to Egress: Strategic Exploitation of the Cellular Processes by HIV-1. Front Microbiol 11, 559792 (2020). 33343516 PMC7746852 · DOI
  7. [9]Deeks, S. G., Overbaugh, J., Phillips, A. & Buchbinder, S. HIV infection. Nat. Rev. Dis. Prim. 1, 15035 (2015). 27188527 · DOI
  8. [11]Boxus, M. et al. The HTLV-1 Tax interactome. Retrovirology 5, 76–76 (2008). 18702816 PMC2533353 · DOI
  9. [12]Currer, R. et al. HTLV tax: a fascinating multifunctional co-regulator of viral and cellular pathways. Front. Microbiol. 3, 406 (2012). 23226145 PMC3510432 · DOI · Paper page
  10. [13]Ernzen, K. J. & Panfil, A. R. Regulation of HTLV-1 transformation. Biosci. Rep.42, 10.1042/BSR20211921 (2022). PMC8919135 35169839 · DOI
  11. [14]Bergman, A. C., Bjornberg, O., Nord, J., Nyman, P. O. & Rosengren, A. M. The protein p30, encoded at the gag-pro junction of mouse mammary tumor virus, is a dUTPase fused with a nucleocapsid protein. Virology 204, 420–424, (1994). 8091672 · DOI · Paper page
  12. [15]Hizi, A. et al. Characterization of mouse mammary tumor virus gag-pro gene products and the ribosomal frameshift site by protein sequencing. Proc. Natl Acad. Sci. 84, 7041–7045 (1987). 2823251 PMC299225 · DOI
  13. [16]Hizi, A. et al. Analysis of gag proteins from mouse mammary tumor virus. J. Virol. 63, 2543–2549 (1989). 2542570 PMC250722 · DOI
  14. [17]Choi, Y., Kappler, J. W. & Marrack, P. A superantigen encoded in the open reading frame of the 3’ long terminal repeat of mouse mammary tumour virus. Nature 350, 203–207 (1991). 1706480 · DOI
  15. [18]Okeoma, C. M., Lovsin, N., Peterlin, B. M. & Ross, S. R. APOBEC3 inhibits mouse mammary tumour virus replication. Nature 445, 927–930 (2007). 17259974 · DOI
  16. [19]Okeoma, C. M., Petersen, J. & Ross, S. R. Expression of murine APOBEC3 alleles in different mouse strains and their effect on mouse mammary tumor virus infection. J. Virol. 83, 3029–3038 (2009). 19153233 PMC2655539 · DOI
  17. [20]Hizi, A. & Herzig, E. dUTPase: the frequently overlooked enzyme encoded by many retroviruses. Retrovirology 12, 70 (2015). 26259899 PMC4531489 · DOI · Paper page
  18. [21]Finke, D. & Acha-Orbea, H. Differential migration of in vivo primed B and T lymphocytes to lymphoid and non-lymphoid organs. Eur. J. Immunol. 31, 2603–2611 (2001). 11536158 · DOI
  19. [22]Golovkina, T. V., Chervonsky, A., Dudley, J. P. & Ross, S. R. Transgenic mouse mammary tumor virus superantigen expression prevents viral infection. Cell 69, 637–645 (1992). 1316806 · DOI
  20. [23]Golovkina, T. V., Dudley, J. P. & Ross, S. R. B and T cells are required for mouse mammary tumor virus spread within the mammary gland. J. Immunol. 161, 2375–2382 (1998). 9725233 · DOI
  21. [24]Mertz, J. A., Lozano, M. M. & Dudley, J. P. Rev and Rex proteins of human complex retroviruses function with the MMTV Rem-responsive element. Retrovirology 6, 10 (2009). 19192308 PMC2661877 · DOI
  22. [26]Coffin, J. M., Hughes, S. H. & Varmus, H. E. Retroviral Virions and Genomes--Retroviruses (Cold Spring Harbor Laboratory Press, 1997). 21433348
  23. [27]Günzburg, W. H. & Salmons, B. Factors controlling the expression of mouse mammary tumour virus. Biochem J. 283, 625–632 (1992). 1317161 PMC1130929 · DOI · Paper page
  24. [29]Bramblett, D. et al. A redundant nuclear protein binding site contributes to negative regulation of the mouse mammary tumor virus long terminal repeat. J. Virol. 69, 7868–7876 (1995). 7494299 PMC189731 · DOI
  25. [30]Liu, J., Barnett, A., Neufeld, E. J. & Dudley, J. P. Homeoproteins CDP and SATB1 interact: potential for tissue-specific regulation. Mol. Cell. Biol. 19, 4918–4926 (1999). 10373541 PMC84297 · DOI
  26. [31]Zhu, Q., Maitra, U., Johnston, D., Lozano, M. & Dudley, J. P. The homeodomain protein CDP regulates mammary-specific gene transcription and tumorigenesis. Mol. Cell. Biol. 24, 4810–4823 (2004). 15143175 PMC416401 · DOI
  27. [32]Zhu, Q., Gregg, K., Lozano, M., Liu, J. & Dudley, J. P. CDP is a repressor of mouse mammary tumor virus expression in the mammary gland. J. Virol. 74, 6348–6357 (2000). 10864645 PMC112141 · DOI
  28. [33]Cordingley, M. G., Riegel, A. T. & Hager, G. L. Steroid-dependent interaction of transcription factors with the inducible promoter of mouse mammary tumor virus in vivo. Cell 48, 261–270 (1987). 3026639 · DOI
  29. [34]Truss, M., Bartsch, J., Schelbert, A., Haché, R. J. & Beato, M. Hormone induces binding of receptors and transcription factors to a rearranged nucleosome on the MMTV promoter in vivo. EMBO J. 14, 1737–1751 (1995). 7737125 PMC398267 · DOI
  30. [35]Majors, J. & Varmus, H. E. A small region of the mouse mammary tumor virus long terminal repeat confers glucocorticoid hormone regulation on a linked heterologous gene. Proc. Natl Acad. Sci. USA 80, 5866–5870 (1983). 6310597 PMC390176 · DOI
  31. [36]Mok, E., Golovkina, T. V. & Ross, S. R. A mouse mammary tumor virus mammary gland enhancer confers tissue-specific but not lactation-dependent expression in transgenic mice. J. Virol. 66, 7529–7532 (1992). 1331537 PMC240463 · DOI
  32. [37]Akhlaq, S. et al. A cis-Acting Element Downstream of the Mouse Mammary Tumor Virus Major Splice Donor Critical for RNA Elongation and Stability. J. Mol. Biol. 430, 4307–4324 (2018). 30179605 PMC6193448 · DOI · Paper page
  33. [38]Greatorex, J. S., Palmer, E. A., Pomerantz, R. J., Dangerfield, J. A. & Lever, A. M. L. Mutation of the Rev-binding loop in the human immunodeficiency virus 1 leader causes a replication defect characterized by altered RNA trafficking and packaging. J. Gen. Virol. 87, 3039–3044 (2006). 16963763 · DOI
  34. [39]Gallego, J. et al. Rev binds specifically to a purine loop in the SL1 region of the HIV-1 leader RNA. J. Biol. Chem. 278, 40385–40391 (2003). 12851400 · DOI
  35. [40]Bannwarth, S. & Gatignol, A. HIV-1 TAR RNA: the target of molecular interactions between the virus and its host. Curr. HIV Res. 3, 61–71 (2005). 15638724 · DOI
  36. [41]Kashanchi, F. & Brady, J. N. Transcriptional and post-transcriptional gene regulation of HTLV-1. Oncogene 24, 5938–5951 (2005). 16155601 · DOI
  37. [42]Aktar, S. J. et al. Structural basis of genomic RNA (gRNA) dimerization and packaging determinants of mouse mammary tumor virus (MMTV). Retrovirology 11, 1–21 (2014). 25394412 PMC4264320 · DOI · Paper page
  38. [43]Mustafa, F. et al. The bifurcated stem loop 4 (SL4) is crucial for efficient packaging of mouse mammary tumor virus (MMTV) genomic RNA. RNA Biol. 15, 1047–1059 (2018). 29929424 PMC6161677
  39. [44]Chameettachal, A. et al. A purine loop and the primer binding site are critical for the selective encapsidation of mouse mammary tumor virus genomic RNA by Pr77Gag. Nucleic Acids Res. 49, 4668–4688 (2021). 33836091 PMC8096270 · DOI · Paper page
  40. [45]Geddes, V. E. V. et al. HTLV-1 Tax activates HIV-1 transcription in latency models. Virology 504, 45–51 (2017). 28152383 · DOI
  41. [46]Shackleford, G. M. & Varmus, H. E. Construction of a clonable, infectious, and tumorigenic mouse mammary tumor virus provirus and a derivative genetic vector. Proc. Natl Acad. Sci. 85, 9655–9659 (1988). 2849114 PMC282828 · DOI
  42. [47]Das, A. T., Harwig, A. & Berkhout, B. The HIV-1 Tat protein has a versatile role in activating viral transcription. J. Virol. 85, 9506–9516 (2011). 21752913 PMC3165771 · DOI
  43. [48]Rice, A. P. The HIV-1 Tat Protein: Mechanism of Action and Target for HIV-1 Cure Strategies. Curr. Pharm. Des. 23, 4098–4102 (2017). 28677507 PMC5700838 · DOI
  44. [49]Core, L. & Adelman, K. Promoter-proximal pausing of RNA polymerase II: a nexus of gene regulation. Genes Dev. 33, 960–982 (2019). 31123063 PMC6672056 · DOI
  45. [50]Whelan, M. & Pelchat, M. Role of RNA Polymerase II Promoter-Proximal Pausing in Viral Transcription. Viruses14, 2029 (2022). PMC9503719 36146833
  46. [51]Liu, X. et al. Human Virus Transcriptional Regulators. Cell 182, 24–37 (2020). 32649876 PMC7346790 · DOI
  47. [52]Lacombe, B., Morel, M., Margottin-Goguet, F. & Ramirez, B. C. Specific Inhibition of HIV Infection by the Action of Spironolactone in T Cells. J. Virol. 90, 10972–10980 (2016). 27681137 PMC5110165 · DOI
  48. [53]Mori, L. et al. The XPB Subunit of the TFIIH Complex Plays a Critical Role in HIV-1 Transcription and XPB Inhibition by Spironolactone Prevents HIV-1 Reactivation from Latency. J Virol95, 10.1128/JVI.01247-20 (2021). PMC7851559 33239456 · DOI
  49. [54]Martella, C. et al. Human T-Cell Lymphotropic Virus Type 1 Transactivator Tax Exploits the XPB Subunit of TFIIH during Viral Transcription. J. Virol.94, 10.1128/JVI.02171-19 (2020). PMC7108837 32024775 · DOI · Paper page
  50. [55]Carstens, E. Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses (2009). Arch. Virol. 155, 133–146 (2010). 19960211 PMC7086975 · DOI
  51. [56]Katzourakis, A., Tristem, M., Pybus, O. G. & Gifford, R. J. Discovery and analysis of the first endogenous lentivirus. Proc. Natl Acad. Sci. USA 104, 6261–6265 (2007). 17384150 PMC1851024 · DOI
  52. [57]Jacks, T., Townsley, K., Varmus, H. E. & Majors, J. Two efficient ribosomal frameshifting events are required for synthesis of mouse mammary tumor virus gag-related polyproteins. Proc. Natl Acad. Sci. USA 84, 4298–4302 (1987). 3035577 PMC305072 · DOI
  53. [58]Medstrand, P. & Blomberg, J. Characterization of novel reverse transcriptase encoding human endogenous retroviral sequences similar to type A and type B retroviruses: differential transcription in normal human tissues. J. Virol. 67, 6778–6787 (1993). 7692084 PMC238119 · DOI
  54. [59]Dervan, E., Bhattacharyya, D. D., McAuliffe, J. D., Khan, F. H. & Glynn, S. A. Ancient Adversary - HERV-K (HML-2) in Cancer. Front Oncol. 11, 658489 (2021). 34055625 PMC8155577 · DOI
  55. [60]Zhou, Q., Li, T. & Price, D. H. RNA polymerase II elongation control. Annu Rev. Biochem 81, 119–143 (2012). 22404626 PMC4273853 · DOI
  56. [61]McNamara, R. P. & Bacon, C. W. & D’Orso, I. Transcription elongation control by the 7SK snRNP complex: Releasing the pause. Cell Cycle 15, 2115–2123 (2016). 27152730 PMC4993427 · DOI
  57. [62]Fujinaga, K. et al. Dynamics of human immunodeficiency virus transcription: P-TEFb phosphorylates RD and dissociates negative effectors from the transactivation response element. Mol. Cell. Biol. 24, 787–795 (2004). 14701750 PMC343783 · DOI
  58. [63]Yamada, T. et al. P-TEFb-mediated phosphorylation of hSpt5 C-terminal repeats is critical for processive transcription elongation. Mol. Cell 21, 227–237 (2006). 16427012 · DOI
  59. [64]Li, Y., Liu, X., Fujinaga, K., Gross, J. D. & Frankel, A. D. Enhanced NF-kappaB activation via HIV-1 Tat-TRAF6 cross-talk. Sci. Adv. 10, eadi4162 (2024). 38241362 PMC10798561 · DOI
  60. [65]Nyborg, J. K. et al. Interaction of host cell proteins with the human T-cell leukemia virus type I transcriptional control region. II. A comprehensive map of protein-binding sites facilitates construction of a simple chimeric promoter responsive to the viral tax2 gene product. J. Biol. Chem. 265, 8237–8242 (1990). 2186038 · DOI
  61. [66]Barnhart, M. K., Connor, L. M. & Marriott, S. J. Function of the human T-cell leukemia virus type 1 21-base-pair repeats in basal transcription. J. Virol. 71, 337–344 (1997). 8985355 PMC191056 · DOI
  62. [67]Winter, H. Y. & Marriott, S. J. Human T-cell leukemia virus type 1 Tax enhances serum response factor DNA binding and alters site selection. J. Virol. 81, 6089–6098 (2007). 17376895 PMC1900302 · DOI
  63. [68]Rizvi, T. A. et al. Role of a heterologous retroviral transport element in the development of genetic complementation assay for mouse mammary tumor virus (MMTV) replication. Virology 385, 464–472 (2009). 19157480 · DOI · Paper page
  64. [69]Adachi, A. et al. Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J. Virol. 59, 284–291 (1986). 3016298 PMC253077 · DOI

Cited by

Sorted by citations

Authors
Khader, T. A., Ahmad, W., Akhlaq, S., Panicker, N. G., Gull, B., Baby, J., Rizvi, T. A., & Mustafa, F.
Affiliations
United Arab Emirates University (AE)
Corresponding author
  • Rizvi, Tahir A.
  • Mustafa, Farah
ORCID
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2024-11-16
Volume
7
Issue
1
Pages
1521-1521
ISSN
2399-3642 (ISSN-L)
DOI
10.1038/s42003-024-07139-9
PMC
PMC11569226
OpenAlex
W4404432845
Cited by
4
References
4
Citations by year
2026: 1 · 2025: 3
FWCI
0.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Biology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Advanced Technology Research Council (VRI-20-10)
  • United Arab Emirates University (12M136, 12M103, 31R140)
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 › Genomics and Chromatin Dynamics
Keywords
mouse mammary tumor virus, transcriptional activation, HIV-1 Tat protein, HTLV-1 Tax, P-TEFb, transcriptional regulation, betaretrovirus, retroviral vectors, gene therapy
MeSH terms
Animals, Humans, Mammary Tumor Virus, Mouse, Transcriptional Activation, Gene Expression Regulation, Viral, Gene Products, tax, Mice, tat Gene Products, Human Immunodeficiency Virus, HEK293 Cells

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