Recombinant vaccinia virus K3L gene product prevents activation of double-stranded RNA-dependent, initiation factor 2 alpha-specific protein kinase

Carroll, Kate; Elroy‐Stein, Orna; Moss, Bernard; Jagus, Rosemary

doi:10.1016/s0021-9258(18)31463-7

Cited by 171 publications

(23 citation statements)

References 2 publications

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“…These proteins prevent binding of IFN to cellular receptors, emphasizing the importance of this cytokine in the host's response to poxvirus infection [ 39 , 40 ]. In addition, the products of the K3L and E3L genes, encoded by vaccinia virus, prevent the inhibition of IFN-induced protein synthesis [ 41 , 42 ]. It is noteworthy that full genomic sequences for both Brazilian isolates used in this study are not yet available.…”

Section: Discussionmentioning

confidence: 99%

Zoonotic vaccinia virus strains belonging to different genetic clades exhibit immunomodulation abilities that are proportional to their virulence

Lourenço

Chinália

Henriques

et al. 2021

Virol J

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Background The vaccinia virus (VACV) isolates, Guarani P1 virus (GP1V) and Passatempo virus (PSTV), were isolated during zoonotic outbreaks in Brazil. Each one of them belongs to two different VACV clades, defined by biological aspects that include virulence in mice and phylogenetic analysis. Considering that information about how vaccinia viruses from different groups elicit immune responses in animals is scarce, we investigated such responses in mice infected either by GP1V (group 2) or PSTV (group 1), using VACV Western Reserve strain (VACV-WR) as control. Methods The severity of the infections was evaluated in BALB/c mice considering diverse clinical signs and defined scores, and the immune responses triggered by GP1V and PSTV infections were analysed by immune cell phenotyping and intra-cytoplasmic cytokines detection. Results We detected a reduction in total lymphocytes (CD3 +), macrophages (CD14 +), and NK cells (CD3-CD49 +) in animals infected with VACV-WR or GP1V. The VACV-WR and GP1V viruses, belonging to the most virulent group in a murine model, were able to down-modulate the cell immune responses upon mice infection. In contrast, PSTV, a virus considered less virulent in a murine model, showed little ability to down-modulate the mice immune responses. Mice infected with VACV-WR and GP1V viruses presented significant weight loss and developed lesions in their spleens, as well as damage to liver and lungs whereas mice infected with PSTV developed only moderate clinical signs. Conclusions Our results suggest that VACV immunomodulation in vivo is clade-related and is proportional to the strain’s virulence upon infection. Our data corroborate the classification of the different Brazilian VACV isolates into clades 1 and 2, taking into account not only phylogenetic criteria, but also clinical and immunological data.

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Section: Discussionmentioning

confidence: 99%

Zoonotic vaccinia virus strains belonging to different genetic clades exhibit immunomodulation abilities that are proportional to their virulence

Lourenço

Chinália

Henriques

et al. 2021

Virol J

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“…to increase the activity of human cell-derived CFPS systems, but had not previously been tested in CHO CFPS (Mikami et al, 2006a(Mikami et al, , 2010bBurgenson et al, 2018). GADD34 is a regulator that recruits protein phosphatase 1, leading to dephosphorylation of eIF2α (Novoa et al, 2001), and K3L is a viral protein that acts as a pseudo-substrate, reducing phosphorylation of eIF2α (Carroll et al, 1993).…”

Section: Supplementing Reactions With Purified Gadd34 And/or K3l Leads To An Increase In Expression Yieldmentioning

confidence: 99%

Design, Development and Optimization of a Functional Mammalian Cell-Free Protein Synthesis Platform

Heide

Buldum

Moya-Ramírez

et al. 2021

Front. Bioeng. Biotechnol.

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In this paper, we describe the stepwise development of a cell-free protein synthesis (CFPS) platform derived from cultured Chinese hamster ovary (CHO) cells. We provide a retrospective summary of the design challenges we faced, and the optimized methods developed for the cultivation of cells and the preparation of translationally active lysates. To overcome low yields, we developed procedures to supplement two accessory proteins, GADD34 and K3L, into the reaction to prevent deactivation of the translational machinery by phosphorylation. We compared different strategies for implementing these accessory proteins including two variants of the GADD34 protein to understand the potential trade-offs between yield and ease of implementation. Addition of the accessory proteins increased yield of turbo Green Fluorescent Protein (tGFP) by up to 100-fold depending on which workflow was used. Using our optimized protocols as a guideline, users can successfully develop their own functional CHO CFPS system, allowing for broader application of mammalian CFPS.

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“…Here, phosphorylation of the eukaryotic translation initiation factor eIF2a by host PKR inhibits eIF2a activity. As access to translation machinery is critical for viral replication, poxviruses use eIF2‐mimics like the viral protein K3L to inhibit PKR [60–63], and thus prevent translation from being inhibited. Evolutionary analysis reveals that primate hosts have diversified PKR amino acid residues targeted by K3L, and K3L in turn has mutated amino acids, likely in order to keep pace with changes in host PKR.…”

Section: Real‐time Observation Of Transient Expansion Of Viral Virulence Factor K3lmentioning

confidence: 99%

Conservation lost: host‐pathogen battles drive diversification and expansion of gene families

Lažetić

Troemel

2020

The FEBS Journal

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One of the strongest drivers in evolution is the struggle to survive a hostpathogen battle. This pressure selects for diversity among the factors directly involved in this battle, including virulence factors deployed by pathogens, their corresponding host targets, and host immune factors. A logical outcome of this diversification is that over time, the sequence of many immune factors will not be evolutionarily conserved across a broad range of species. Thus, while universal sequence conservation is often hailed as the hallmark of the importance of a particular gene, the immune system does not necessarily play by these rules when defending against coevolving pathogens. This loss of sequence conservation is in contrast to many signaling pathways in development and basic cell biology that are not targeted by pathogens. In addition to diversification, another consequence of host-pathogen battles can be an amplification in gene number, thus leading to large gene families that have sequence relatively specific to a particular strain, species, or clade. Here we highlight this general theme across a variety of pathogen virulence factors and host immune factors. We summarize the wide range and number across species of these expanded, lineage-specific host-pathogen factors including ubiquitin ligases, nucleotide-binding leucine-rich repeat receptors, GTPases, and proteins without obvious biochemical function but that nonetheless play key roles in immunity.

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Recombinant vaccinia virus K3L gene product prevents activation of double-stranded RNA-dependent, initiation factor 2 alpha-specific protein kinase

Cited by 171 publications

References 2 publications

Zoonotic vaccinia virus strains belonging to different genetic clades exhibit immunomodulation abilities that are proportional to their virulence

Zoonotic vaccinia virus strains belonging to different genetic clades exhibit immunomodulation abilities that are proportional to their virulence

Design, Development and Optimization of a Functional Mammalian Cell-Free Protein Synthesis Platform

Conservation lost: host‐pathogen battles drive diversification and expansion of gene families

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