Insights from structural studies of the cardiovirus 2A protein

Caliskan, Neva; Hill, C.P.

doi:10.1042/bsr20210406

Cited by 6 publications

(5 citation statements)

References 98 publications

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“…It should additionally be noted that the YxxxxLΦ motif (129–135 aa), earlier predicted as an eIF4E-binding sequence mimicking the 4E-BP functional motif [ 38 ], remained intact in Δ2A and Zfmut&Δ2A mutants. However, current data on the structure of the 2A protein indicate that this site does not interact with eIF4E, due to structural differences between it and the eIF4E-binding domain of 4E-BP [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…2A acts as a trans-activator for −1 frameshifting inside the 2B-coding region, which makes it a regulator of downstream protein synthesis [ 32 ]. Structure resolution of the 2A discovered part of the protein that is responsible for that process [ 42 ], the arginine loop (95–100 a.a.), which was deleted in our mutants Δ2A and Zfmut&Δ2A. During the -1 frameshifting that occurs in the middle of the viral cycle (6–8 h.p.i., L929 cells), the 2B* protein translates on the alternative frame [ 2 ], and non-structural proteins 2B, 2C, 3AB, 3C, and 3D synthesize with less efficiency.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive Elucidation of the Role of L and 2A Security Proteins on Cell Death during EMCV Infection

Ivin,

Butusova,

Gladneva

et al. 2024

Viruses

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The EMCV L and 2A proteins are virulence factors that counteract host cell defense mechanisms. Both L and 2A exhibit antiapoptotic properties, but the available data were obtained in different cell lines and under incomparable conditions. This study is aimed at checking the role of these proteins in the choice of cell death type in three different cell lines using three mutants of EMCV lacking functional L, 2A, and both proteins together. We have found that both L and 2A are non-essential for viral replication in HeLa, BHK, and RD cell lines, as evidenced by the viability of the virus in the absence of both functional proteins. L-deficient infection led to the apoptotic death of HeLa and RD cells, and the necrotic death of BHK cells. 2A-deficient infection induced apoptosis in BHK and RD cells. Infection of HeLa cells with the 2A-deficient mutant was finalized with exclusive caspase-dependent death with membrane permeabilization, morphologically similar to pyroptosis. We also demonstrated that inactivation of both proteins, along with caspase inhibition, delayed cell death progression. The results obtained demonstrate that proteins L and 2A play a critical role in choosing the path of cell death during infection, but the result of their influence depends on the properties of the host cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comprehensive Elucidation of the Role of L and 2A Security Proteins on Cell Death during EMCV Infection

Ivin,

Butusova,

Gladneva

et al. 2024

Viruses

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“…While TMEV is known to target sialic acids in the gastrointestinal tract in in vitro settings [ 50 , 51 , 52 ], the receptors used by TMEV during an in vivo CNS viral infection are yet to be determined. Viral binding to the host cell surface receptor leads to a viral uncoating [ 1 , 31 , 53 , 54 ], allowing the release of the viral genome into the cytoplasm. Based on studies of other members of the picornavirus family, it is suggested that TMEV may utilize receptor-mediated endocytosis to enter the host cell.…”

Section: Tmev Infectionmentioning

confidence: 99%

The Contribution of Microglia and Brain-Infiltrating Macrophages to the Pathogenesis of Neuroinflammatory and Neurodegenerative Diseases during TMEV Infection of the Central Nervous System

DePaula-Silva

2024

Viruses

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The infection of the central nervous system (CNS) with neurotropic viruses induces neuroinflammation and is associated with the development of neuroinflammatory and neurodegenerative diseases, including multiple sclerosis and epilepsy. The activation of the innate and adaptive immune response, including microglial, macrophages, and T and B cells, while required for efficient viral control within the CNS, is also associated with neuropathology. Under healthy conditions, resident microglia play a pivotal role in maintaining CNS homeostasis. However, during pathological events, such as CNS viral infection, microglia become reactive, and immune cells from the periphery infiltrate into the brain, disrupting CNS homeostasis and contributing to disease development. Theiler’s murine encephalomyelitis virus (TMEV), a neurotropic picornavirus, is used in two distinct mouse models: TMEV-induced demyelination disease (TMEV-IDD) and TMEV-induced seizures, representing mouse models of multiple sclerosis and epilepsy, respectively. These murine models have contributed substantially to our understanding of the pathophysiology of MS and seizures/epilepsy following viral infection, serving as critical tools for identifying pharmacological targetable pathways to modulate disease development. This review aims to discuss the host–pathogen interaction during a neurotropic picornavirus infection and to shed light on our current understanding of the multifaceted roles played by microglia and macrophages in the context of these two complexes viral-induced disease.

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“…In both viruses, a predicted RNA stem-loop structure is present that could act as a stimulatory RNA but is located too far 3 ′ of the slippery sequence to interact with the ribosome (spacer is 13-14 nucleotides). Subsequently, protein 2A was identified as the viral cofactor, binding to the stem-loop and forming a protein-RNA complex that is highly active in PRF stimulation (98,99). A feature of the nsp2/2B * signal is that it allows temporal regulation of virus gene expression.…”

Section: Proteins and Peptidesmentioning

confidence: 99%

Structural and Functional Insights into Viral Programmed Ribosomal Frameshifting

Hill

Brierley

2023

Annu. Rev. Virol.

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Protein synthesis by the ribosome is the final stage of biological information transfer and represents an irreversible commitment to gene expression. Accurate translation of messenger RNA is therefore essential to all life, and spontaneous errors by the translational machinery are highly infrequent (∼1/100,000 codons). Programmed −1 ribosomal frameshifting (−1PRF) is a mechanism in which the elongating ribosome is induced at high frequency to slip backward by one nucleotide at a defined position and to continue translation in the new reading frame. This is exploited as a translational regulation strategy by hundreds of RNA viruses, which rely on −1PRF during genome translation to control the stoichiometry of viral proteins. While early investigations of −1PRF focused on virological and biochemical aspects, the application of X-ray crystallography and cryo–electron microscopy (cryo-EM), and the advent of deep sequencing and single-molecule approaches have revealed unexpected structural diversity and mechanistic complexity. Molecular players from several model systems have now been characterized in detail, both in isolation and, more recently, in the context of the elongating ribosome. Here we provide a summary of recent advances and discuss to what extent a general model for −1PRF remains a useful way of thinking. Expected final online publication date for the Annual Review of Virology, Volume 10 is September 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Insights from structural studies of the cardiovirus 2A protein

Cited by 6 publications

References 98 publications

Comprehensive Elucidation of the Role of L and 2A Security Proteins on Cell Death during EMCV Infection

Comprehensive Elucidation of the Role of L and 2A Security Proteins on Cell Death during EMCV Infection

The Contribution of Microglia and Brain-Infiltrating Macrophages to the Pathogenesis of Neuroinflammatory and Neurodegenerative Diseases during TMEV Infection of the Central Nervous System

Structural and Functional Insights into Viral Programmed Ribosomal Frameshifting

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