The GTPase Domain of MX2 Interacts with the HIV-1 Capsid, Enabling Its Short Isoform to Moderate Antiviral Restriction

Betancor, Gilberto; Dicks, Matthew D. J.; Jiménez-Guardeño, Jose M.; Ali, Nafees F; Apolonia, Luis; Malim, Michael H.

doi:10.1016/j.celrep.2019.10.009

Cited by 31 publications

(49 citation statements)

References 52 publications

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“…IFNs activate hundreds of genes known as IFN-stimulated genes (ISGs) through the Janus kinase-signal transducer/activator of transcription (JAK/STAT) signaling pathway, which provides a complete antiviral response targeting all stages of viruses' replicative cycles [ 32 , 36 ]. For example, MX2 (the IFN-induced GTP-binding protein) prevents the replication of human immunodeficiency virus (HIV) after its association with the capsid [ 37 ] and IFITMs (IFN-induced transmembrane protein) probably modify the membrane structure and the pH of endosomes by inhibiting the fusion of viral membranes with the cell membrane [ 38 ]. In addition to many roles in regulating the immune response [ 38 ], it is demonstrated that IFITM proteins prevent the entry of SARS-CoV and MERS-CoV into the cell [ 39 , 40 ].…”

Section: Interferons and Coronavirusesmentioning

confidence: 99%

Prevention and treatment of COVID-19: Focus on interferons, chloroquine/hydroxychloroquine, azithromycin, and vaccine

Bakadia¹,

He²,

Souho³

et al. 2021

Biomedicine & Pharmacotherapy

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Section: Interferons and Coronavirusesmentioning

confidence: 99%

Prevention and treatment of COVID-19: Focus on interferons, chloroquine/hydroxychloroquine, azithromycin, and vaccine

Bakadia¹,

He²,

Souho³

et al. 2021

Biomedicine & Pharmacotherapy

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“…The most downregulated protein was interferon-induced GTP-binding protein Mx1 (MX1). MX1 exhibits antiviral properties and plays an important role against a wide range of RNA viruses [ 30 , 31 ]. Protein mono-ADP-ribosyltransferase (PARP9) was also downregulated and is involved in interferon-mediated antiviral defenses [ 32 ].…”

Section: Resultsmentioning

confidence: 99%

The Loss of HLA-F/KIR3DS1 Ligation Is Mediated by Hemoglobin Peptides

Hò

Hiemisch

Pich

et al. 2020

IJMS

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The human leukocyte antigen (HLA)-Ib molecule, HLA-F, is known as a CD4+ T-cell protein and mediator of HIV progression. While HLA-Ia molecules do not have the chance to select and present viral peptides for immune recognition due to protein downregulation, HLA-F is upregulated. Post HIV infection, HLA-F loses the affinity to its activating receptor KIR3DS1 on NK cells leading to progression of the HIV infection. Several studies aimed to solve the question of the biophysical interface between HLA ligands and their cognate receptors. It became clear that even an invariant HLA molecule can be structurally modified by the variability of the bound peptide. We recently discovered the ability of HLA-F to select and present peptides and the HLA-F allele-specific peptide selection from the proteomic content using soluble HLA (sHLA) technology and a sophisticated MS method. We established recombinant K562 cells that express membrane-bound HLA-F*01:01, 01:03 or 01:04 complexes. While a recombinant soluble form of KIR3DS1 did not bind to the peptide-HLA-F complexes, acid elution of the peptides resulted in the presentation of HLA-F open conformers, and the binding of the soluble KIR3DS1 receptor increased. We used CD4+/HIV− and CD4+/HIV+ cells and performed an MS proteome analysis. We could detect hemoglobin as significantly upregulated in CD4+ T-cells post HIV infection. The expression of cellular hemoglobin in nonerythroid cells has been described, yet HLA-Ib presentation of hemoglobin-derived peptides is novel. Peptide sequence analysis from HLA-F allelic variants featured hemoglobin peptides as dominant and shared. The reciprocal experiment of binding hemoglobin peptide fractions to the HLA-F open conformers resulted in significantly diminished receptor recognition. These results underpin the molecular involvement of HLA-F and its designated peptide ligand in HIV immune escape.

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“…While the precise mechanism of MX2 inhibition of HIV-1 infection remains to be determined, the viral capsid is a critical target of MX2 restriction, since capsid-specific replacement mutations can escape MX2-mediated inhibition [ 213 , 214 , 215 , 216 , 217 ]. MX2 interacts with in vitro assembled capsid and capsid-nucleocapsid structures and two binding domains have been identified in the N-terminus and in the GTPase region ( Figure 3 ) [ 72 , 73 , 218 , 219 , 220 ].…”

Section: Retroviral Restriction Factorsmentioning

confidence: 99%

“…The determination that MX2 inhibits viral nuclear import is based on the analysis of the two transcriptional isoforms in humans that result from alternative use of an internal start codon [ 221 ]. The shorter isoform lacks the N-terminal nuclear localization signal and does not show any antiviral activity, but interferes with the restrictive activity of the longer isoform through competitive capsid binding [ 72 , 213 , 214 ]. Moreover, the longer isoform localizes to the nuclear periphery while the shorter isoform is cytoplasmic as is MX1 [ 222 ].…”

Section: Retroviral Restriction Factorsmentioning

confidence: 99%

“…Schematic representation identifies positively selected residues (down arrows) found through analyses of Fv1 in rodents and primate genes for TRIM5α, APOBEC3G, SAMHD1 and MX2 [ 64 , 65 , 66 , 67 , 68 ]. The red bars indicate the binding regions for Vif in APOBEC3G, Vpx in SAMHDI and capsid in TRIM5α, TRIMCyp and MX2 [ 69 , 70 , 71 , 72 , 73 , 74 ]. MHR, major homology region; CypA, cyclophilin A; BSE, bundle signaling element; NLS, nuclear localization signal; N, unstructured amino terminal domain.…”

Section: Figurementioning

confidence: 99%

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Retroviral Restriction Factors and Their Viral Targets: Restriction Strategies and Evolutionary Adaptations

Boso

Kozak

2020

Microorganisms

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The evolutionary conflict between retroviruses and their vertebrate hosts over millions of years has led to the emergence of cellular innate immune proteins termed restriction factors as well as their viral antagonists. Evidence accumulated in the last two decades has substantially increased our understanding of the elaborate mechanisms utilized by these restriction factors to inhibit retroviral replication, mechanisms that either directly block viral proteins or interfere with the cellular pathways hijacked by the viruses. Analyses of these complex interactions describe patterns of accelerated evolution for these restriction factors as well as the acquisition and evolution of their virus-encoded antagonists. Evidence is also mounting that many restriction factors identified for their inhibition of specific retroviruses have broader antiviral activity against additional retroviruses as well as against other viruses, and that exposure to these multiple virus challenges has shaped their adaptive evolution. In this review, we provide an overview of the restriction factors that interfere with different steps of the retroviral life cycle, describing their mechanisms of action, adaptive evolution, viral targets and the viral antagonists that evolved to counter these factors.

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The GTPase Domain of MX2 Interacts with the HIV-1 Capsid, Enabling Its Short Isoform to Moderate Antiviral Restriction

Cited by 31 publications

References 52 publications

Prevention and treatment of COVID-19: Focus on interferons, chloroquine/hydroxychloroquine, azithromycin, and vaccine

Prevention and treatment of COVID-19: Focus on interferons, chloroquine/hydroxychloroquine, azithromycin, and vaccine

The Loss of HLA-F/KIR3DS1 Ligation Is Mediated by Hemoglobin Peptides

Retroviral Restriction Factors and Their Viral Targets: Restriction Strategies and Evolutionary Adaptations

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