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MMTV RNA packaging requires an extended long-range interaction for productive Gag binding to packaging signals

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Prabhu, Suresha G., Pillai, Vineeta N., Ali, Lizna Mohamed, Vivet-Boudou, Valérie, Chameettachal, Akhil, Bernacchi, Serena, Mustafa, Farah, Marquet, Roland +1 more·2024·PLOS Biology
DOI 10.1371/journal.pbio.3002827PMC PMC11449360
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Abstract

The packaging of genomic RNA (gRNA) into retroviral particles relies on the specific recognition by the Gag precursor of packaging signals (Psi), which maintain a complex secondary structure through long-range interactions (LRIs). However, it remains unclear whether the binding of Gag to Psi alone is enough to promote RNA packaging and what role LRIs play in this process. Using mouse mammary tumor virus (MMTV), we investigated the effects of mutations in 4 proposed LRIs on gRNA structure and function. Our findings revealed the presence of an unsuspected extended LRI, and hSHAPE revealed that maintaining a wild-type–like Psi structure is crucial for efficient packaging. Surprisingly, filter-binding assays demonstrated that most mutants, regardless of their packaging capability, exhibited significant binding to Pr77 Gag, suggesting that Gag binding to Psi is insufficient for efficient packaging. Footprinting experiments indicated that efficient RNA packaging is promoted when Pr77 Gag binds to 2 specific sites within Psi, whereas binding elsewhere in Psi does not lead to efficient packaging. Taken together, our results suggest that the 3D structure of the Ps i/Pr77 Gag complex regulates the assembly of viral particles around gRNA, enabling effective discrimination against other viral and cellular RNAs that may also bind Gag efficiently.

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  • In MMTV, disrupting U5-U5 LRIs abolishes gRNA packaging despite preserving Gag-binding elsewhere, indicating that packaging requires specific RNA structures in the correct three-dimensional context for Gag to bind to the primary binding sites.

    “in the case of MMTV, disrupting U5–U5 LRIs has been shown to abolish gRNA packaging despite preserving Gag-binding elsewhere, indicating that packaging requires specific RNA structures in the correct three-dimensional context for Gag to bind to the primary binding sites”

    From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Prabhu et al. 2024

  • Similar LRI-mediated RNA rearrangements have been observed in MPMV, FIV, and MMTV where complementary interactions between U5 and downstream sequences stabilize the overall RNA secondary structure facilitating gRNA packaging.

    “Similar LRI-mediated RNA rearrangements have been observed in MPMV, FIV, and MMTV where complementary interactions between U5 and downstream sequences stabilize the overall RNA secondary structure facilitating gRNA packaging”

    From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Prabhu et al. 2024

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Cited by

Sorted by citations

Authors
Prabhu, S. G., Pillai, V. N., Ali, L. M., Vivet-Boudou, V., Chameettachal, A., Bernacchi, S., Mustafa, F., Marquet, R., & Rizvi, T. A.
Affiliations
  • United Arab Emirates University (AE)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
  • Marquet, Roland
  • Rizvi, Tahir A.
ORCID
Venue
PLOS Biology
Publisher
Public Library of Science (PLoS)
Published
2024-10-03
Volume
22
Issue
10
Pages
e3002827
ISSN
  • 1544-9173 (ISSN-L)
  • 1545-7885
DOI
10.1371/journal.pbio.3002827
PMC
PMC11449360
OpenAlex
W4403092448
Cited by
2
References
6
Citations by year
2026: 1 · 2025: 1
FWCI
0.27
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • College of Medicine and Health Sciences, United Arab Emirates University (NP-24-09)
  • United Arab Emirates University (UPAR-12M103)
  • Centre National de la Recherche Scientifique (RetroPack International Research project)
  • Department of Education and Knowledge (AARE20‐344, AARE20-344)
  • ASPIREMRIAD (VRI‐20‐10)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
Keywords
mouse mammary tumor virus, RNA packaging, packaging signal, long-range interactions, Gag, genomic RNA, RNA secondary structure
MeSH terms
Viral Genome Packaging, Animals, Humans, Mammary Tumor Virus, Mouse, Mutation, Nucleic Acid Conformation, Protein Binding, RNA, Viral, Gene Products, gag, Virus Assembly, Mice, HEK293 Cells

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