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Regulation of HIV-2 Vpx/Vpr expression by the poly-proline motif: Enhancement of protein dimerization and translation.

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Title: Regulation of HIV-2 Vpx/Vpr expression by the poly-proline motif: Enhancement of protein dimerization and translation.
Authors: Nakamura Y; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan., Ahagon-Edamura A; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan., Koga R; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan., Shimagaki K; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan., Uesugi M; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan., Fujino H; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan., Beyri B; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan., Arakaki Y; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan., Ciftci H; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan; Department of Molecular Biology and Genetics, Burdur Mehmet Akif Ersoy University, Burdur, 15200, Turkey; Research and Development, Science Farm Ltd., Kumamoto, 862-0976, Japan., Masunaga T; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan., Tateishi H; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan., Otsuka M; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan; Research and Development, Science Farm Ltd., Kumamoto, 862-0976, Japan., Yamaguchi Y; Environmental Safety Center, Kumamoto University, Kumamoto, 860-8555, Japan., Fujita M; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan; Department of Molecular Biology and Genetics, Burdur Mehmet Akif Ersoy University, Burdur, 15200, Turkey. Electronic address: mfujita@kumamoto-u.ac.jp.
Source: Virology [Virology] 2026 Oct; Vol. 623, pp. 111016. Date of Electronic Publication: 2026 Jun 29.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Academic Press Country of Publication: United States NLM ID: 0110674 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-0341 (Electronic) Linking ISSN: 00426822 NLM ISO Abbreviation: Virology Subsets: MEDLINE
Imprint Name(s): Original Publication: New York, Academic Press.
MeSH Terms: Viral Regulatory and Accessory Proteins*/genetics , Viral Regulatory and Accessory Proteins*/metabolism , Viral Regulatory and Accessory Proteins*/chemistry , HIV-2*/genetics , HIV-2*/physiology , HIV-2*/metabolism , vpr Gene Products, Human Immunodeficiency Virus*/genetics , vpr Gene Products, Human Immunodeficiency Virus*/metabolism , vpr Gene Products, Human Immunodeficiency Virus*/chemistry , Peptides*/metabolism , Peptides*/genetics , Peptides*/chemistry , Protein Multimerization* , Gene Expression Regulation, Viral* , Protein Biosynthesis*, Macrophages/virology ; Humans ; Amino Acid Motifs ; Cell Line ; Virus Replication
Abstract: Human immunodeficiency virus type 2 (HIV-2) encodes the Vpx and Vpr proteins. Although these proteins are homologous, Vpx is expressed at substantially higher levels than those of Vpr. This difference can be explained by the presence of a zinc-binding site and a poly-proline motif (PPM) consisting of seven consecutive prolines, both of which are present in Vpx but absent in Vpr. This study aims to elucidate the mechanism by which the PPM regulates Vpx/Vpr expression. Experiments using point mutants at positions P108 and P109 (the last proline of the PPM) in Vpx showed that P109 is critical for replication in macrophages and is important for achieving sufficient expression levels and dimerization capacity of the Vpx protein, compared with P108. In contrast, introduction of the PPM into the Vpr protein increased its expression level in an in vitro transcription/translation system while decreasing mRNA expression. In addition, no significant increase in protein stability was detected. These results, together with additional mutational analyses, demonstrate that introduction of the PPM enhances translation of the Vpr protein. In contrast, introduction of the PPM into Human immunodeficiency virus type 1 (HIV-1) Vif did not increase expression levels. Furthermore, a synthetic peptide containing seven consecutive prolines did not bind to immunoprecipitated Vpx protein. Overall, Vpx dimerization is not considered to be caused by dimerization of the PPM region. Collectively, these findings indicate that the PPM of Vpx enhances protein dimerization, leading to increased stability, and that introduction of the PPM into Vpr enhances its translation.
(Copyright © 2026 Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributed Indexing: Keywords: HIV-2; Poly-proline; Protein dimerization; Translation; Vpr; Vpx
Substance Nomenclature: 0 (Viral Regulatory and Accessory Proteins)
0 (VPX protein, Human immunodeficiency virus 2)
0 (vpr Gene Products, Human Immunodeficiency Virus)
25191-13-3 (polyproline)
0 (Peptides)
0 (vpr protein, Human immunodeficiency virus 2)
Entry Date(s): Date Created: 20260707 Date Completed: 20260723 Latest Revision: 20260723
Update Code: 20260724
DOI: 10.1016/j.virol.2026.111016
PMID: 42413395
Database: MEDLINE
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  Data: Regulation of HIV-2 Vpx/Vpr expression by the poly-proline motif: Enhancement of protein dimerization and translation.
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  Data: <searchLink fieldCode="AU" term="%22Nakamura+Y%22">Nakamura Y</searchLink>; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.<br /><searchLink fieldCode="AU" term="%22Ahagon-Edamura+A%22">Ahagon-Edamura A</searchLink>; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.<br /><searchLink fieldCode="AU" term="%22Koga+R%22">Koga R</searchLink>; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.<br /><searchLink fieldCode="AU" term="%22Shimagaki+K%22">Shimagaki K</searchLink>; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.<br /><searchLink fieldCode="AU" term="%22Uesugi+M%22">Uesugi M</searchLink>; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.<br /><searchLink fieldCode="AU" term="%22Fujino+H%22">Fujino H</searchLink>; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.<br /><searchLink fieldCode="AU" term="%22Beyri+B%22">Beyri B</searchLink>; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.<br /><searchLink fieldCode="AU" term="%22Arakaki+Y%22">Arakaki Y</searchLink>; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.<br /><searchLink fieldCode="AU" term="%22Ciftci+H%22">Ciftci H</searchLink>; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan; Department of Molecular Biology and Genetics, Burdur Mehmet Akif Ersoy University, Burdur, 15200, Turkey; Research and Development, Science Farm Ltd., Kumamoto, 862-0976, Japan.<br /><searchLink fieldCode="AU" term="%22Masunaga+T%22">Masunaga T</searchLink>; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.<br /><searchLink fieldCode="AU" term="%22Tateishi+H%22">Tateishi H</searchLink>; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.<br /><searchLink fieldCode="AU" term="%22Otsuka+M%22">Otsuka M</searchLink>; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan; Research and Development, Science Farm Ltd., Kumamoto, 862-0976, Japan.<br /><searchLink fieldCode="AU" term="%22Yamaguchi+Y%22">Yamaguchi Y</searchLink>; Environmental Safety Center, Kumamoto University, Kumamoto, 860-8555, Japan.<br /><searchLink fieldCode="AU" term="%22Fujita+M%22">Fujita M</searchLink>; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan; Department of Molecular Biology and Genetics, Burdur Mehmet Akif Ersoy University, Burdur, 15200, Turkey. Electronic address: mfujita@kumamoto-u.ac.jp.
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  Data: <searchLink fieldCode="JN" term="%220110674%22">Virology</searchLink> [Virology] 2026 Oct; Vol. 623, pp. 111016. <i>Date of Electronic Publication: </i>2026 Jun 29.
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– Name: Abstract
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  Data: Human immunodeficiency virus type 2 (HIV-2) encodes the Vpx and Vpr proteins. Although these proteins are homologous, Vpx is expressed at substantially higher levels than those of Vpr. This difference can be explained by the presence of a zinc-binding site and a poly-proline motif (PPM) consisting of seven consecutive prolines, both of which are present in Vpx but absent in Vpr. This study aims to elucidate the mechanism by which the PPM regulates Vpx/Vpr expression. Experiments using point mutants at positions P<superscript>108</superscript> and P<superscript>109</superscript> (the last proline of the PPM) in Vpx showed that P<superscript>109</superscript> is critical for replication in macrophages and is important for achieving sufficient expression levels and dimerization capacity of the Vpx protein, compared with P<superscript>108</superscript>. In contrast, introduction of the PPM into the Vpr protein increased its expression level in an in vitro transcription/translation system while decreasing mRNA expression. In addition, no significant increase in protein stability was detected. These results, together with additional mutational analyses, demonstrate that introduction of the PPM enhances translation of the Vpr protein. In contrast, introduction of the PPM into Human immunodeficiency virus type 1 (HIV-1) Vif did not increase expression levels. Furthermore, a synthetic peptide containing seven consecutive prolines did not bind to immunoprecipitated Vpx protein. Overall, Vpx dimerization is not considered to be caused by dimerization of the PPM region. Collectively, these findings indicate that the PPM of Vpx enhances protein dimerization, leading to increased stability, and that introduction of the PPM into Vpr enhances its translation.<br /> (Copyright © 2026 Elsevier Inc. All rights reserved.)
– Name: Abstract
  Label: Competing Interests
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  Data: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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  Data: <i>Keywords: </i>HIV-2; Poly-proline; Protein dimerization; Translation; Vpr; Vpx
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  Data: 0 (Viral Regulatory and Accessory Proteins)<br />0 (VPX protein, Human immunodeficiency virus 2)<br />0 (vpr Gene Products, Human Immunodeficiency Virus)<br />25191-13-3 (polyproline)<br />0 (Peptides)<br />0 (vpr protein, Human immunodeficiency virus 2)
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        Value: 10.1016/j.virol.2026.111016
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
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        StartPage: 111016
    Subjects:
      – SubjectFull: Macrophages virology
        Type: general
      – SubjectFull: Humans
        Type: general
      – SubjectFull: Amino Acid Motifs
        Type: general
      – SubjectFull: Cell Line
        Type: general
      – SubjectFull: Virus Replication
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      – SubjectFull: Viral Regulatory and Accessory Proteins genetics
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      – SubjectFull: Viral Regulatory and Accessory Proteins metabolism
        Type: general
      – SubjectFull: Viral Regulatory and Accessory Proteins chemistry
        Type: general
      – SubjectFull: HIV-2 genetics
        Type: general
      – SubjectFull: HIV-2 physiology
        Type: general
      – SubjectFull: HIV-2 metabolism
        Type: general
      – SubjectFull: vpr Gene Products, Human Immunodeficiency Virus genetics
        Type: general
      – SubjectFull: vpr Gene Products, Human Immunodeficiency Virus metabolism
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