HIV-1 Gag Blocks Selenite-Induced Stress Granule Assembly by Altering the mRNA Cap-Binding Complex

Cinti, Alessandro; Sage, Valerie Le; Ghanem, Marwan; Mouland, Andrew J.

doi:10.1128/mbio.00329-16

Cited by 25 publications

(23 citation statements)

References 48 publications

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“…In our previous work, we have shown that HIV-1 disrupts the canonical type I SG assembly in an eIF2α phosphorylation (eIF2α-P) independent manner via an interaction with the eukaryotic elongation factor eEF2 with the capsid (CA) domain on the Gag polyprotein (Abrahamyan et al 2010;Valiente-Echeverria et al 2014). We also demonstrated that Gag is able to block the assembly of type II, noncanonical SGs by reducing the amount of hypophosphorylated 4EBP1 associated with the 5 ′ cap potentially through an interaction with its target, eIF4E (Cinti et al 2016). Interestingly, a recent study has reported that the expression of the HIV-1 NC alone leads to the assembly of SGs (Yu et al 2016).…”

Section: Introductionmentioning

confidence: 87%

HIV-1 NC-induced stress granule assembly and translation arrest are inhibited by the dsRNA binding protein Staufen1

Rao

Cinti

Temzi

et al. 2017

RNA

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The nucleocapsid (NC) is an N-terminal protein derived from the HIV-1 Gag precursor polyprotein, pr55 NC possesses key functions at several pivotal stages of viral replication. For example, an interaction between NC and the host double-stranded RNA-binding protein Staufen1 was shown to regulate several steps in the viral replication cycle, such as Gag multimerization and genomic RNA encapsidation. In this work, we observed that the overexpression of NC leads to the induction of stress granule (SG) assembly. NC-mediated SG assembly was unique as it was resistant to the SG blockade imposed by the HIV-1 capsid (CA), as shown in earlier work. NC also reduced host cell mRNA translation, as judged by a puromycylation assay of de novo synthesized proteins, and this was recapitulated in polysome profile analyses. Virus production was also found to be significantly reduced. Finally, Staufen1 expression completely rescued the blockade to NC-mediated SG assembly, global mRNA translation as well as virus production. NC expression also resulted in the phosphorylation of protein kinase R (PKR) and eIF2α, and this was inhibited with Staufen1 coexpression. This work sheds light on an unexpected function of NC in host cell translation. A comprehensive understanding of the molecular mechanisms by which a fine balance of the HIV-1 structural proteins NC and CA act in concert with host proteins such as Staufen1 to modulate the host stress response will aid in the development of new antiviral therapeutics.

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Section: Introductionmentioning

confidence: 87%

HIV-1 NC-induced stress granule assembly and translation arrest are inhibited by the dsRNA binding protein Staufen1

Rao

Cinti

Temzi

et al. 2017

RNA

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“…Because HIV-1 Gag was recently reported to inhibit SG formation 33,34 , we also tested the effects of treating HeLa.YFP-A3G or HeLa.YFP-TIA1 biosensor cells with Ars at 31 hpi when NL4-3 Gag expression in HeLa cells is relatively high ( e.g. , see 31 ).…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, HIV-1 42,43 , other retroviruses 44,45 , and endogenous retroelements including LINEs 46 and yeast Ty elements 47 are thought to exploit non-membranous RNP complexes related to PBs/SGs in order to compartmentalize activities including mRNA translation and genome packaging. Regarding suppression, intriguing recent work from Mouland and colleagues has shown HIV-1 to actively inhibit SG formation, proposed to reduce the potential for stress signaling triggered by Gag NC interacting with host RNA species 33,34 . While we did not observe overt SG suppression in this study (Figs.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 RNA genomes initiate host protein packaging in the cytosol independently of Gag capsid proteins

Becker

Evans

Benner

et al. 2019

Preprint

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17HIV-1 RNA genomes interact with diverse RNA binding proteins in the cytoplasm 18 including antiviral factor APOBEC3G (A3G) that, in the absence of viral Vif proteins, is 19 packaged into virions. When and where genome-A3G interactions are initiated in the host 20 cell is unknown. Here we use quantitative long-term (>24 h) live cell fluorescence video 21 microscopy and a new in-cell RNA-protein interaction assay (the "IC-IP") to describe 22 subcellular viral and A3G trafficking behaviors over the entire HIV-1 productive phase. 23Among other findings, we demonstrate that genome-A3G interactions are initiated in the 24 cytosol soon if not immediately after genome nuclear export; that A3G-genome 25 interactions are sufficiently strong so that tethering either factor to membranes inhibits 26 trafficking of the reciprocal binding partner; and that selective recognition of genomes 27 promotes consistent delivery of A3G to sites of virion assembly. Further elucidation of 28 RNA signature(s) detected by A3G may inform development of RNA-targeted antivirals. 29 RNA-and NC-dependent15-20. However, the relative contributions of genomes vs. host 50RNAs to this process remains controversial. On the one hand, A3G-RNA binding is 51 relatively promiscuous, with A3G incorporated into virus particles even when packageable 52 genomes are not expressed17,19. On the other hand, A3G incorporation levels are 53 moderately enhanced when genomes are present16,21; and A3G has been shown to 54 exhibit selective RNA-binding characteristics19,22 including a reported preference for G-55 rich segments of the HIV-1 genome20. 56Where and when A3G interfaces with Gag and/or genomes in the cell has also been 57 under investigation for some time with conflicting results. At steady-state, A3G is 58 distributed throughout the cytosol (the aqueous phase of the cytoplasm) and accumulates 59 to high levels at non-membranous cytoplasmic sites of mRNA decay known as processing 60 bodies (PBs)23,24. Cytosolic A3G is also rapidly re-localized to sites of translational 61 repression known as stress granules (SGs) in response to heat shock or oxidative 62 stress23,24. Initial studies proposed a functional link between PBs and A3G's antiviral 63 activity23,25,26. By contrast, more recent work has shown visible PBs to have little to no 64 discernible relevance to the HIV-1 life cycle27,28. 65The dynamic and complex nature of cytoplasmic RNA trafficking during HIV-1 virion 66 genesis may have obscured consistent prior observations made in fixed cells, 67 emphasizing a need for real-time characterization the host RBP response to HIV-1 68 infection at subcellular resolution. Accordingly, herein we set out to comprehensively 69 define the behaviors of HIV-1 RNA genomes, Gag, A3G, and additional PB and SG 70 markers over the entire viral productive phase using long-term (>24h) live cell video 71 microscopy. Our results expose single-cell A3G degradation and trafficking behaviors in 72 the presence or absence of Vif; and show that HIV-1 infection has little to no ne...

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“…Others have reported that HIV-1 Gag is associated with RNA granule proteins including Staufen1 (53, 54), AGO2 (55), and MOV10 (56). However, HIV-1 Gag is not found in stress granules (54), whose formation is induced by stress; nevertheless, Gag has been shown to modulate formation of stress granules (54, 57, 58). Similarly, a recent study reported that HIV-1 Gag does not co-localize with P bodies by fluorescent microscopy (59).…”

Section: Discussionmentioning

confidence: 99%

The ABCE1 capsid assembly pathway is conserved between primate lentiviruses and the non-primate lentivirus feline immunodeficiency virus

Reed¹,

Westergreen²,

Barajas

et al. 2017

Preprint

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24During immature capsid assembly in cells, the Gag protein of HIV-1 and other primate lentiviruses 25 co-opts a host RNA granule, forming a pathway of assembly intermediates that contains host components, 26including two cellular enzymes shown to facilitate assembly, ABCE1 and DDX6. Here we asked whether 27 a non-primate lentivirus, feline immunodeficiency virus (FIV), also forms such RNA-granule-derived 28 intracellular capsid assembly intermediates. First, we found that, unlike for HIV-1, the FIV completed 29 immature capsid and the largest putative assembly intermediate are unstable during analysis. Next, we 30 identified in situ cross-linking conditions that overcame this problem and revealed the presence of FIV 31

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HIV-1 Gag Blocks Selenite-Induced Stress Granule Assembly by Altering the mRNA Cap-Binding Complex

Cited by 25 publications

References 48 publications

HIV-1 NC-induced stress granule assembly and translation arrest are inhibited by the dsRNA binding protein Staufen1

HIV-1 NC-induced stress granule assembly and translation arrest are inhibited by the dsRNA binding protein Staufen1

HIV-1 RNA genomes initiate host protein packaging in the cytosol independently of Gag capsid proteins

The ABCE1 capsid assembly pathway is conserved between primate lentiviruses and the non-primate lentivirus feline immunodeficiency virus

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