Cyclophilin A Interacts with HIV-1 Vpr and Is Required for Its Functional Expression

Zander, Kerstin; Sherman, Michael P.; Tessmer, Uwe; Bruns, Karsten; Wray, Victor; Prechtel, Alexander; Schubert, Evelyn; Henklein, Peter; Luban, Jeremy; Neidleman, Jason; Greene, Warner C.; Schubert, Ulrich S.

doi:10.1074/jbc.m305414200

Cited by 84 publications

(82 citation statements)

References 73 publications

(115 reference statements)

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“…S3). We then examined the activity of Vpr in primary human macrophages, in which Vpr has been reported to give an advantage to the virus in multicycle infection assays (6,(8)(9)(10)(11). The role of HLTF has not yet been examined in such nondividing cells.…”

Section: Resultsmentioning

confidence: 99%

“…Vpr is not required for infection of most cell lines or primary CD4 + T cells (5)(6)(7). A replication defect for vpr-deleted viruses has been reported in dendritic cells and macrophages, with important donor-to-donor variability (6,(8)(9)(10)(11). It was recently suggested that Vpr favors infection of macrophages by counteracting a restriction factor targeting Env expression and viral release (12).…”

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confidence: 99%

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HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

Lahouassa

Blondot

Chauveau

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Viruses often interfere with the DNA damage response to better replicate in their hosts. The human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) protein has been reported to modulate the activity of the DNA repair structure-specific endonuclease subunit (SLX4) complex and to promote cell cycle arrest. Vpr also interferes with the base-excision repair pathway by antagonizing the uracil DNA glycosylase (Ung2) enzyme. Using an unbiased quantitative proteomic screen, we report that Vpr down-regulates helicase-like transcription factor (HLTF), a DNA translocase involved in the repair of damaged replication forks. Vpr subverts the DDB1-cullin4-associatedfactor 1 (DCAF1) adaptor of the Cul4A ubiquitin ligase to trigger proteasomal degradation of HLTF. This event takes place rapidly after Vpr delivery to cells, before and independently of Vpr-mediated G2 arrest. HLTF is degraded in lymphocytic cells and macrophages infected with Vpr-expressing HIV-1. Our results reveal a previously unidentified strategy for HIV-1 to antagonize DNA repair in host cells.HIV | restriction factor | DNA repair | Vpr target | SILAC

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

Lahouassa

Blondot

Chauveau

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The major resonances of the all-trans-proline-containing peptides were determined in 50% TFE solution for the three Vpr fragments (Vpr 1-40 , Vpr [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] , and Vpr [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] ) and their Asn mutants (Vpr 1-20 P5,10,14N and Vpr [21][22][23][24][25][26][27][28][29][30][31]…”

Section: Methodsmentioning

confidence: 99%

“…We propose that this unusual cis/trans phenomenon contributes to the high flexibility of Vpr and that this so far unreported phenomenon indicates a requirement for a cellular cis/trans peptidyl-prolyl isomerase (PPIase) activity to regulate folding of Vpr in vivo. Indeed in an accompanying paper (38) we report that the N terminus of Vpr interacts with a major host cell PPIase cyclophilin A (CypA) that, like Vpr, is specifically incorporated into HIV-1 virions and that this CypA-Vpr interaction regulates expression and biological function of Vpr.…”

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confidence: 99%

Structural Characterization of the HIV-1 Vpr N Terminus

Bruns

Fossen

Wray

et al. 2003

Journal of Biological Chemistry

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The 96-residue human immunodeficiency virus (HIV) accessory protein Vpr serves manifold functions in the retroviral life cycle including augmentation of viral replication in non-dividing host cells, induction of G 2 cell cycle arrest, and modulation of HIV-induced apoptosis. Using a combination of dynamic light scattering, circular dichroism, and NMR spectroscopy the N terminus of Vpr is shown to be a unique domain of the molecule that behaves differently from the C-terminal domain in terms of self-association and secondary structure folding. Interestingly, the four highly conserved proline residues in the N terminus are predicted to have a high propensity for cis/trans isomerism. Thus the high resolution structure and folding of a synthetic N-terminal peptide (Vpr 1-40 ) and smaller fragments thereof have been investigated. 1 H NMR data indicate Vpr 1-40 possesses helical structure between residues 17-32, and for the first time, this helix, which is bound by proline residues, was observed even in aqueous solution devoid of any detergent supplements. In addition, NMR data revealed that all of the proline residues undergo a cis/ trans isomerism to such an extent that ϳ40% of all Vpr molecules possess at least one proline in a cis conformation. This phenomenon of cis/trans isomerism, which is unprecedented for HIV-1 Vpr, not only provides an explanation for the molecular heterogeneity observed in the full-length molecule but also indicates that in vivo the folding and function of Vpr should depend on a cis/trans-proline isomerase activity, particularly as two of the proline residues in positions 14 and 35 show considerable amounts of cis isomers. This prediction correlates well with our recent observation

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“…The abundance and diversity of single and multidomain immunophilins identified to date underlines the functional versatility of this family, which is further exemplified by the wide range of cellular processes in which they are involved. Nuclear cyclophilin CypH assembles into spliceosomal complexes where it assists with mRNA splicing Ingelfinger et al, 2003); CypA functionally interacts with the major virion-associated HIV accessory protein viral protein R, but also modulates the catalytic activity of interleukin-2 Tyr kinase (Brazin et al, 2002;Zander et al, 2003); CypB exerts its function in the nucleus as a part of the prolactin transcriptional control machinery (Rycyzyn and Clevenger, 2002), but also triggers the integrin-mediated adhesion of peripheral blood T lymphocytes to the extracellular matrix (Allain et al, 2002). FKBP12 constitutes an integral component of well-documented receptors such as the TGFb receptor Type II or calcium channels such as the ryanodine receptor or the inositol 1,4,5-triphosphate receptor.…”

Section: A Twist In the Tale: Convergence Of Immunophilins And Ppiasesmentioning

confidence: 99%