scholarly journals Evolution toward beta common chain receptor usage links the matrix proteins of HIV-1 and its ancestors to human erythropoietin

2020 ◽  
Vol 118 (2) ◽  
pp. e2021366118
Author(s):  
Francesca Caccuri ◽  
Pasqualina D’Ursi ◽  
Matteo Uggeri ◽  
Antonella Bugatti ◽  
Pietro Mazzuca ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Molecular Mimicry ◽  
Cell Types ◽  
Biological Data ◽  
Matrix Proteins ◽  
Target Cells ◽  
Human Erythropoietin ◽  
The Matrix ◽  
The Difference ◽  
Hiv 1

The HIV-1 matrix protein p17 (p17) is a pleiotropic molecule impacting on different cell types. Its interaction with many cellular proteins underlines the importance of the viral protein as a major determinant of human specific adaptation. We previously showed the proangiogenic capability of p17. Here, by integrating functional analysis and receptor binding, we identify a functional epitope that displays molecular mimicry with human erythropoietin (EPO) and promotes angiogenesis through common beta chain receptor (βCR) activation. The functional EPO-like epitope was found to be present in the matrix protein of HIV-1 ancestors SIV originated in chimpanzees (SIVcpz) and gorillas (SIVgor) but not in that of HIV-2 and its ancestor SIVsmm from sooty mangabeys. According to biological data, evolution of the EPO-like epitope showed a clear differentiation between HIV-1/SIVcpz-gor and HIV-2/SIVsmm branches, thus highlighting this epitope on p17 as a divergent signature discriminating HIV-1 and HIV-2 ancestors. P17 is known to enhance HIV-1 replication. Similarly to other βCR ligands, p17 is capable of attracting and activating HIV-1 target cells and promoting a proinflammatory microenvironment. Thus, it is tempting to speculate that acquisition of an epitope on the matrix proteins of HIV-1 ancestors capable of triggering βCR may have represented a critical step to enhance viral aggressiveness and early human-to-human SIVcpz/gor dissemination. The hypothesis that the p17/βCR interaction and βCR abnormal stimulation may also play a role in sustaining chronic activation and inflammation, thus marking the difference between HIV-1 and HIV-2 in term of pathogenicity, needs further investigation.

scholarly journals Analysis of the Viral Elements Required in the Nuclear Import of HIV-1 DNA

2009 ◽  
Vol 84 (2) ◽  
pp. 729-739 ◽  
Author(s):  
Lise Rivière ◽  
Jean-Luc Darlix ◽  
Andrea Cimarelli
Keyword(s):  
Nuclear Import ◽  
Matrix Protein ◽  
Active Phase ◽  
Cell Types ◽  
Target Cells ◽  
Nuclear Pore ◽  
Viral Dna ◽  
The Matrix ◽  
Central Polypurine Tract ◽  
Hiv 1

ABSTRACT HIV-1 possesses an exquisite ability to infect cells independently from their cycling status by undergoing an active phase of nuclear import through the nuclear pore. This property has been ascribed to the presence of karyophilic elements present in viral nucleoprotein complexes, such as the matrix protein (MA); Vpr; the integrase (IN); and a cis-acting structure present in the newly synthesized DNA, the DNA flap. However, their role in nuclear import remains controversial at best. In the present study, we carried out a comprehensive analysis of the role of these elements in nuclear import in a comparison between several primary cell types, including stimulated lymphocytes, macrophages, and dendritic cells. We show that despite the fact that none of these elements is absolutely required for nuclear import, disruption of the central polypurine tract-central termination sequence (cPPT-CTS) clearly affects the kinetics of viral DNA entry into the nucleus. This effect is independent of the cell cycle status of the target cells and is observed in cycling as well as in nondividing primary cells, suggesting that nuclear import of viral DNA may occur similarly under both conditions. Nonetheless, this study indicates that other components are utilized along with the cPPT-CTS for an efficient entry of viral DNA into the nucleus.

scholarly journals Autophagy Inhibitors Do Not Restore Peroxisomal Functions in Cells With the Most Common Peroxisome Biogenesis Defect

2021 ◽  
Vol 9 ◽  
Author(s):  
Femke C. C. Klouwer ◽  
Kim D. Falkenberg ◽  
Rob Ofman ◽  
Janet Koster ◽  
Démi van Gent ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Protein Import ◽  
Therapeutic Option ◽  
Cell Types ◽  
Matrix Proteins ◽  
Peroxisome Biogenesis ◽  
Metabolic Functions ◽  
Minimal Improvement ◽  
Different Cell Types ◽  
Autophagy Inhibition

Peroxisome biogenesis disorders within the Zellweger spectrum (PBD-ZSDs) are most frequently associated with the c.2528G>A (p.G843D) mutation in the PEX1 gene (PEX1-G843D), which results in impaired import of peroxisomal matrix proteins and, consequently, defective peroxisomal functions. A recent study suggested that treatment with autophagy inhibitors, in particular hydroxychloroquine, would be a potential therapeutic option for PBD-ZSD patients carrying the PEX1-G843D mutation. Here, we studied whether autophagy inhibition by chloroquine, hydroxychloroquine and 3-methyladenine indeed can improve peroxisomal functions in four different cell types with the PEX1-G843D mutation, including primary patient cells. Furthermore, we studied whether autophagy inhibition may be the mechanism underlying the previously reported improvement of peroxisomal functions by L-arginine in PEX1-G843D cells. In contrast to L-arginine, we observed no improvement but a worsening of peroxisomal metabolic functions and peroxisomal matrix protein import by the autophagy inhibitors, while genetic knock-down of ATG5 and NBR1 in primary patient cells resulted in only a minimal improvement. Our results do not support the use of autophagy inhibitors as potential treatment for PBD-ZSD patients, whereas L-arginine remains a therapeutically promising compound.

scholarly journals Matrix and Envelope Coevolution Revealed in a Patient Monitored since Primary Infection with Human Immunodeficiency Virus Type 1

2009 ◽  
Vol 83 (19) ◽  
pp. 9875-9889 ◽  
Author(s):  
Elodie Beaumont ◽  
Daniela Vendrame ◽  
Bernard Verrier ◽  
Emmanuelle Roch ◽  
François Biron ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Matrix Protein ◽  
Immunodeficiency Virus ◽  
The Matrix ◽  
Hiv 1

ABSTRACT Lentiviruses, including human immunodeficiency virus type 1 (HIV-1), typically encode envelope glycoproteins (Env) with long cytoplasmic tails (CTs). The strong conservation of CT length in primary isolates of HIV-1 suggests that this factor plays a key role in viral replication and persistence in infected patients. However, we report here the emergence and dominance of a primary HIV-1 variant carrying a natural 20-amino-acid truncation of the CT in vivo. We demonstrated that this truncation was deleterious for viral replication in cell culture. We then identified a compensatory amino acid substitution in the matrix protein that reversed the negative effects of CT truncation. The loss or rescue of infectivity depended on the level of Env incorporation into virus particles. Interestingly, we found that a virus mutant with defective Env incorporation was able to spread by cell-to-cell transfer. The effects on viral infectivity of compensation between the CT and the matrix protein have been suggested by in vitro studies based on T-cell laboratory-adapted virus mutants, but we provide here the first demonstration of the natural occurrence of similar mechanisms in an infected patient. Our findings provide insight into the potential of HIV-1 to evolve in vivo and its ability to overcome major structural alterations.

scholarly journals HIV-1 p17 Matrix Protein Interacts with Heparan Sulfate Side Chain of CD44v3, Syndecan-2, and Syndecan-4 Proteoglycans Expressed on Human Activated CD4+ T Cells Affecting Tumor Necrosis Factor α and Interleukin 2 Production

2011 ◽  
Vol 286 (22) ◽  
pp. 19541-19548 ◽  
Author(s):  
Maria A. De Francesco ◽  
Manuela Baronio ◽  
Claudio Poiesi
Keyword(s):  
T Cells ◽  
Heparan Sulfate ◽  
Matrix Protein ◽  
Interleukin 2 ◽  
Fluorescence Analysis ◽  
Heparin Binding ◽  
The Matrix ◽  
C And N ◽  
Factor Α ◽  
Hiv 1

HIV-1 p17 contains C- and N-terminal sequences with positively charged residues and a consensus cluster for heparin binding. We have previously demonstrated by affinity chromatography that HIV-1 p17 binds strongly to heparin-agarose at physiological pH and to human activated CD4+ T cells. In this study we demonstrated that the viral protein binds to heparan sulfate side chains of syndecan-2, syndecan-4, and CD44v3 purified from HeLa cells and that these heparan sulfate proteoglycans (HSPGs) co-localize with HIV-1 p17 on activated human CD4+ T cells by confocal fluorescence analysis. Moreover, we observed a stimulatory or inhibitory activity when CD4+ T cells were activated with mitogens together with nanomolar or micromolar concentrations of the matrix protein.

scholarly journals The matrix protein CCN1 (CYR61) induces apoptosis in fibroblasts

2005 ◽  
Vol 171 (3) ◽  
pp. 559-568 ◽  
Author(s):  
Viktor Todorovicç ◽  
Chih-Chiun Chen ◽  
Nissim Hay ◽  
Lester F. Lau
Keyword(s):  
Cell Adhesion ◽  
Cell Survival ◽  
Matrix Protein ◽  
De Novo ◽  
Cell Types ◽  
Cellular Interaction ◽  
Cytochrome C Release ◽  
The Matrix ◽  
Promote Cell Survival ◽  
Integrin Α6β1

Integrin-mediated cell adhesion to extracellular matrix proteins is known to promote cell survival, whereas detachment from the matrix can cause rapid apoptotic death in some cell types. Contrary to this paradigm, we show that fibroblast adhesion to the angiogenic matrix protein CCN1 (CYR61) induces apoptosis, whereas endothelial cell adhesion to CCN1 promotes cell survival. CCN1 induces fibroblast apoptosis through its adhesion receptors, integrin α6β1 and the heparan sulfate proteoglycan (HSPG) syndecan-4, triggering the transcription-independent p53 activation of Bax to render cytochrome c release and activation of caspase-9 and -3. Neither caspase-8 activity nor de novo transcription or translation is required for this process. These results show that cellular interaction with a specific matrix protein can either induce or suppress apoptosis in a cell type–specific manner and that integrin α6β1-HSPGs can function as receptors to induce p53-dependent apoptosis.

scholarly journals The unique degradation pathway of the PTS2 receptor, Pex7, is dependent on the PTS receptor/coreceptor, Pex5 and Pex20

2014 ◽  
Vol 25 (17) ◽  
pp. 2634-2643 ◽  
Author(s):  
Danielle Hagstrom ◽  
Changle Ma ◽  
Soumi Guha-Polley ◽  
Suresh Subramani
Keyword(s):  
Matrix Protein ◽  
Protein Import ◽  
Degradation Pathway ◽  
Matrix Proteins ◽  
Receptor Recycling ◽  
Wild Type ◽  
The Matrix ◽  
Peroxisomal Targeting ◽  
Targeting Signals ◽  
The Stability

Peroxisomal matrix protein import uses two peroxisomal targeting signals (PTSs). Most matrix proteins use the PTS1 pathway and its cargo receptor, Pex5. The PTS2 pathway is dependent on another receptor, Pex7, and its coreceptor, Pex20. We found that during the matrix protein import cycle, the stability and dynamics of Pex7 differ from those of Pex5 and Pex20. In Pichia pastoris, unlike Pex5 and Pex20, Pex7 is constitutively degraded in wild-type cells but is stabilized in pex mutants affecting matrix protein import. Degradation of Pex7 is more prevalent in cells grown in methanol, in which the PTS2 pathway is nonessential, in comparison with oleate, suggesting regulation of Pex7 turnover. Pex7 must shuttle into and out of peroxisomes before it is polyubiquitinated and degraded by the proteasome. The shuttling of Pex7, and consequently its degradation, is dependent on the receptor recycling pathways of Pex5 and Pex20 and relies on an interaction between Pex7 and Pex20. We also found that blocking the export of Pex20 from peroxisomes inhibits PTS1-mediated import, suggesting sharing of limited components in the export of PTS receptors/coreceptors. The shuttling and stability of Pex7 are divergent from those of Pex5 and Pex20, exemplifying a novel interdependence of the PTS1 and PTS2 pathways.

scholarly journals HEED, the Product of the Human Homolog of the MurineeedGene, Binds to the Matrix Protein of HIV-1

1999 ◽  
Vol 274 (3) ◽  
pp. 1635-1645 ◽  
Author(s):  
Régis Peytavi ◽  
Saw See Hong ◽  
Bernard Gay ◽  
Arnaud Dupuy d’Angeac ◽  
Luc Selig ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Human Homolog ◽  
The Matrix ◽  
Hiv 1

Proteins From Oyster Shell: Biomineralization Regulators and Commercial Polymer Analogs

1999 ◽  
Vol 599 ◽  
Author(s):  
A. P. Wheeler ◽  
C. S. Sikes
Keyword(s):  
Crystal Growth ◽  
Aspartic Acid ◽  
Large Scale ◽  
Matrix Protein ◽  
Gene Families ◽  
Eastern Oyster ◽  
Matrix Proteins ◽  
The Matrix

AbstractMolluscan shell is a composite made up of μm-sized CaCO3 crystals and an organic phase (matrix). This report outlines our studies on the structure and activities of matrix proteins isolated from the inner calcite layer of shell of the Eastern oyster, including their cellular origin and structure and their relationship to the crystalline mineral phase. In addition, we present results of the synthesis and commercialization of polypeptide polymers which are based on the structure and activities of the oyster proteins. Extracted shell proteins are polyanionic and range in size from relatively small soluble forms to those which are crosslinked and insoluble. The soluble forms are capable of adsorbing to calcite in vitro and in the process changing its growth habit and acting as threshold growth inhibitors. Their function in vivo is not understood, but they may serve to control shell crystal morphology. The insoluble protein forms gels readily and may serve to provide resiliency to the shell and, from in vitro and in situ observations, appears to serve as a site for nucleation of crystals. However, from studies in vitro, these gels do not lower the energy of activation for nucleation, as previously expected. Matrix protein aggregates are identifiable by AFM on the surface of crystals, but as such do not serve as nucleation sites for new crystal growth. If the aggregates are removed, then ectopic crystal growth proceeds readily revealing orientation of the underlying crystals. All the matrix proteins contain domains rich in aspartic acid, are heavily phosphorylated, crossreact in antibody studies and may belong to a limited number of gene families with individuals modified post-synthesis. The proteins are made by a specialized group of cells located primarily some distance from the growing edge of the shell and appear to be assembled into sheets soon after secretion. Soluble anti-scalants and crosslinked insoluble water absorbents have been developed based on the structure and activity of the matrix proteins. These are primarily poly(aspartates) which can be made in large scale via thermal polycondensation of aspartic acid. The soluble forms are commercially used as biodegradable water treatment chemicals among other applications.

The central domain of the matrix protein of HIV-1: influence on protein structure and virus infectivity

2004 ◽  
Vol 385 (3-4) ◽  
Author(s):  
A.-D. Ellenrieder ◽  
W. Kremer ◽  
B. Kattenbeck ◽  
O. Hantschel ◽  
G. Horn ◽  
...  
Keyword(s):  
Protein Structure ◽  
Matrix Protein ◽  
Virus Infectivity ◽  
Central Domain ◽  
The Matrix ◽  
Hiv 1

scholarly journals Redundant Roles for Nucleocapsid and Matrix RNA-Binding Sequences in Human Immunodeficiency Virus Type 1 Assembly

2005 ◽  
Vol 79 (22) ◽  
pp. 13839-13847 ◽  
Author(s):  
David E. Ott ◽  
Lori V. Coren ◽  
Tracy D. Gagliardi
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Matrix Protein ◽  
Particle Production ◽  
Rna Binding ◽  
Immunodeficiency Virus ◽  
The Matrix ◽  
Hiv 1

ABSTRACT RNA appears to be required for the assembly of retroviruses. This is likely due to binding of RNA by multiple Gags, which in turn organizes and stabilizes the Gag-Gag interactions that form the virion. While the nucleocapsid (NC) domain is the most conspicuous RNA-binding region of the human immunodeficiency virus type 1 (HIV-1) Gag polyprotein, we have previously shown that NC is not strictly required for efficient particle production. To determine if an RNA requirement for HIV-1 assembly exists, we analyzed virions produced by an NC deletion mutant for the presence of RNA. The results revealed that virions without NC still contained significant amounts of RNA. Since these packaged RNAs are probably incorporated by other RNA-binding sequences in Gag, an RNA-binding site in the matrix protein (MA) of Gag was mutated. While this mutation did not interfere with HIV-1 replication, a construct with both MA and NC mutations (MX/NX) failed to produce particles. The MX/NX mutant was rescued in trans by coassembly with several forms of Gag: wild-type Gag, either of the single-mutant Gags, or Gag truncations that contain MA or NC sequences. Addition of basic sequences to the MX/NX mutant partially restored particle production, consistent with a requirement for Gag-RNA binding in addition to Gag-Gag interactions. Together, these results support an RNA-binding requirement for Gag assembly, which relies on binding of RNA by MA or NC sequences to condense, organize, and stabilize the HIV-1 Gag-Gag interactions that form the virion.

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