HIV-1 Nef Impairs Heterotrimeric G-protein Signaling by Targeting Gαi2 for Degradation through Ubiquitination

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation.

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“…This would lead to the disruption of the host’s immune response. A similar mechanism was reported for HIV-1 [ 41 ].…”

Section: Discussionsupporting

confidence: 73%

Data and Text Mining Help Identify Key Proteins Involved in the Molecular Mechanisms Shared by SARS-CoV-2 and HIV-1

et al. 2020

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“…Seemingly counterproductively to the benefit of infecting migratory target cells, HIV-1 interferes with a variety of cellular processes that enable cell migration. The multifunctional accessory protein Nef downregulates the expression of several chemokine receptors including, but not limited to the HIV co-receptors CCR5 and CXCR4 (Hrecka et al, 2005; Michel et al, 2005; 2006; Venzke et al, 2006), and impairs the function of G-proteins these receptors use for signal transduction (Chandrasekaran et al, 2012). Nef also disrupts actin-cytoskeletal turnover, necessary to establish stable cell polarity required for fast cellular migration.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Balances the Fitness Costs and Benefits of Disrupting the Host Cell Actin Cytoskeleton Early after Mucosal Transmission

Usmani

Murooka

Déruaz

et al. 2019

Cell Host & Microbe

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SUMMARY: HIV-1 primarily infects T lymphocytes and uses these motile cells as migratory vehicles for effective dissemination in the host. Paradoxically, the virus at the same time disrupts multiple cellular processes underlying lymphocyte motility, seemingly counterproductive to rapid systemic infection. Here we show by intravital microscopy in humanized mice that perturbation of the actin-cytoskeleton via the lentiviral protein Nef, and not changes to chemokine receptor expression or function, is the dominant cause of dysregulated infected T cell motility in lymphoid tissue by preventing stable cellular polarization required for fast migration. Accordingly, disrupting the Nef hydrophobic patch that facilitates actin-cytoskeletal perturbation initially accelerates systemic viral dissemination after female genital transmission. However, the same feature of Nef was subsequently critical for viral persistence in immune-competent hosts. Therefore, a highly conserved activity of lentiviral Nef proteins has dual effects and imposes both fitness costs and benefits on the virus at different stages of infection.

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“…Whether Gα i2 plasma membrane levels undergo physiologically relevant regulation is unknown, however suggesting that they may, Gα i2 is subject to ubiquitination and proteasomal degradation (15). The HIV Nef protein specifically targets this system to degrade Gα i2 in Nef expressing lymphocytes, thereby reducing lymphocyte chemokine responsiveness (16). The second parameter, the rate that Gα subunits hydrolyze GTP to GDP is an intrinsic property of individual G-proteins, but as indicated above this rate is subject to regulation by RGS proteins.…”

mentioning

confidence: 99%

An Essential Role for RGS Protein/Gαi2 Interactions in B Lymphocyte–Directed Cell Migration and Trafficking

Hwang

Park

Harrison

et al. 2015

The Journal of Immunology

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Chemokines engage B lymphocyte surface receptors triggering heterotrimeric G-protein Gαi subunit guanine nucleotide exchange. RGS proteins limit the duration that Gαi subunits remain GTP bound, and the loss of an individual RGS protein typically enhances chemokine receptor signaling. Here, we show that B cells carrying a Gαi2G184S/G184S mutation that disables all RGS protein/Gαi2 interactions exhibit an unexpectedly severe reduction in chemokine receptor signaling. The Gαi2G184S/G184S B cells have markedly elevated basal calcium levels, but poor chemokine induced increases; enhanced non-specific migration, but extremely poor chemotaxis. In striking contrast, the Gαi2G184S/G184S B cells exhibited enhanced sensitivity to Sphingosine 1-Phosphate (S1P). S1P elicited heightened intracellular calcium responses and enhanced S1P-triggered cell migration. Mice with the Gαi2G184S/G184S mutation displayed excessive numbers of germinal center-like structures; abnormal serum immunoglobulin profiles; and aberrant B lymphocyte trafficking. These findings establish an essential role for RGS proteins in B cell chemoattractant signaling and for the proper position of B lymphocytes in lymphoid organs.

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HIV-1 Nef Impairs Heterotrimeric G-protein Signaling by Targeting Gαi2 for Degradation through Ubiquitination

Cited by 8 publications

References 84 publications

Data and Text Mining Help Identify Key Proteins Involved in the Molecular Mechanisms Shared by SARS-CoV-2 and HIV-1

Data and Text Mining Help Identify Key Proteins Involved in the Molecular Mechanisms Shared by SARS-CoV-2 and HIV-1

HIV-1 Balances the Fitness Costs and Benefits of Disrupting the Host Cell Actin Cytoskeleton Early after Mucosal Transmission

An Essential Role for RGS Protein/Gαi2 Interactions in B Lymphocyte–Directed Cell Migration and Trafficking

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