Disentangling the Frames, the State of Research on the Alphavirus 6K and TF Proteins

Ramsey, Jolene; Mukhopadhyay, Suchetana

doi:10.3390/v9080228

Cited by 43 publications

(26 citation statements)

References 152 publications

(254 reference statements)

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“…Nucleocapsids containing one copy of the genome interact with the cytoplasmic tails of viral glycoproteins to promote the budding of new virus particles [ 62 ]. At only 55 amino acids in size, the SINV 6K protein belongs to the viroporin family of proteins and is palmitoylated, helping it to target membranes [ 63 , 64 , 65 , 66 , 67 ]. The 6K protein is also involved in the transport of viral glycoproteins through the vesicular system to the plasma membrane [ 68 , 69 ].…”

Section: Overview Of the Sindbis Virus Life Cyclementioning

confidence: 99%

The Regulation of Translation in Alphavirus-Infected Cells

Carrasco

Sanz

González-Almela

2018

Viruses

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Sindbis virus (SINV) contains an RNA genome of positive polarity with two open reading frames (ORFs). The first ORF is translated from the genomic RNA (gRNA), rendering the viral non-structural proteins, whereas the second ORF is translated from a subgenomic mRNA (sgRNA), which directs the synthesis of viral structural proteins. SINV infection strongly inhibits host cell translation through a variety of different mechanisms, including the phosphorylation of the eukaryotic initiation factor eIF2α and the redistribution of cellular proteins from the nucleus to the cytoplasm. A number of motifs have been identified in SINV sgRNA, including a hairpin downstream of the AUG initiation codon, which is involved in the translatability of the viral sgRNA when eIF2 is inactivated. Moreover, a 3′-UTR motif containing three stem-loop structures is involved in the enhancement of translation in insect cells, but not in mammalian cells. Accordingly, SINV sgRNA has evolved several structures to efficiently compete for the cellular translational machinery. Mechanistically, sgRNA translation involves scanning of the 5′-UTR following a non-canonical mode and without the requirement for several initiation factors. Indeed, sgRNA-directed polypeptide synthesis occurs even after eIF4G cleavage or inactivation of eIF4A by selective inhibitors. Remarkably, eIF2α phosphorylation does not hamper sgRNA translation during the late phase of SINV infection. SINV sgRNA thus constitutes a unique model of a capped viral mRNA that is efficiently translated in the absence of several canonical initiation factors. The present review will mainly focus in the non-canonical mechanism of translation of SINV sgRNA.

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Section: Overview Of the Sindbis Virus Life Cyclementioning

confidence: 99%

The Regulation of Translation in Alphavirus-Infected Cells

Carrasco

Sanz

González-Almela

2018

Viruses

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“…TF then undergoes unique post-translational modifications respective to 6K and is integrated into the envelopes of mature virions (17). Although the biological function of TF is poorly understood (18), it has been hypothesized to function as an ion channel, similar to its 6K counterpart (19). A study with SINV mutants that disrupted production of TF resulted in reduced virus production in mammalian and insect cell lines that was independent of genome replication, particle infectivity, or envelope protein transport to the cellular membrane.…”

mentioning

confidence: 99%

Functional and structural characterization of the chikungunya virus translational recoding signals

Kendra¹,

Advani

Chen³

et al. 2018

Journal of Biological Chemistry

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Climate change and human globalization have spurred the rapid spread of mosquito-borne diseases to naïve populations. One such emerging virus of public health concern is chikungunya virus (CHIKV), a member of the Togaviridae family, genus Alphavirus. CHIKV pathogenesis is predominately characterized by acute febrile symptoms and severe arthralgia, which can persist in the host long after viral clearance. CHIKV has also been implicated in cases of acute encephalomyelitis, and its vertical transmission has been reported. Currently, no FDA-approved treatments exist for this virus. Recoding elements help expand the coding capacity in many viruses and therefore represent potential therapeutic targets in antiviral treatments. Here, we report the molecular and structural characterization of two CHIKV translational recoding signals: a termination codon read-through (TCR) element located between the nonstructural protein 3 and 4 genes and a programmed ؊1 ribosomal frameshift (؊1 PRF) signal located toward the 3 end of the CHIKV 6K gene. Using Dual-Luciferase and immunoblot assays in HEK293T and U87MG mammalian cell lines, we validated and genetically characterized efficient TCR and ؊1 PRF. Analyses of RNA chemical modification data with selective 2-hydroxyl acylation and primer extension (SHAPE) assays revealed that CHIKV ؊1 PRF is stimulated by a tightly structured, triple-stem hairpin element, consistent with previous observations in alphaviruses, and that the TCR signal is composed of a single large multibulged hairpin element. These findings illuminate the roles of RNA structure in translational recoding and provide critical information relevant for design of live-attenuated vaccines against CHIKV and related viruses.

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“…The TF (~8.3 kDa) protein possess the same N terminus as 6 K (61 amino acids~6.6 kDa) but differs by having a longer basic C terminus (~15 residues) instead of a shorter, hydrophobic C terminus found on 6 K [58,87,88]. Unlike other structural proteins, the exact functions of both 6K and TF have not been clearly elucidated [133]. However, studies on other alphaviruses have suggested that these viral accessory proteins mediate membrane permeability and viral budding, and may also be involved in forming ion channels [87,134,135].…”

Section: K/tf Proteinmentioning

confidence: 99%

The Interplay of Viral and Host Factors in Chikungunya Virus Infection: Targets for Antiviral Strategies

Wong

Chu

2018

Viruses

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Chikungunya virus (CHIKV) has re-emerged as one of the many medically important arboviruses that have spread rampantly across the world in the past decade. Infected patients come down with acute fever and rashes, and a portion of them suffer from both acute and chronic arthralgia. Currently, there are no targeted therapeutics against this debilitating virus. One approach to develop potential therapeutics is by understanding the viral-host interactions. However, to date, there has been limited research undertaken in this area. In this review, we attempt to briefly describe and update the functions of the different CHIKV proteins and their respective interacting host partners. In addition, we also survey the literature for other reported host factors and pathways involved during CHIKV infection. There is a pressing need for an in-depth understanding of the interaction between the host environment and CHIKV in order to generate potential therapeutics.

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Disentangling the Frames, the State of Research on the Alphavirus 6K and TF Proteins

Cited by 43 publications

References 152 publications

The Regulation of Translation in Alphavirus-Infected Cells

The Regulation of Translation in Alphavirus-Infected Cells

Functional and structural characterization of the chikungunya virus translational recoding signals

The Interplay of Viral and Host Factors in Chikungunya Virus Infection: Targets for Antiviral Strategies

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