TF protein of Sindbis virus antagonizes host type I interferon responses in a palmitoylation-dependent manner

Rogers, Kai J.; Jones-Burrage, Sara E; Maury, Wendy; Mukhopadhyay, Suchetana

doi:10.1016/j.virol.2020.01.001

Cited by 16 publications

(14 citation statements)

References 53 publications

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“…The TF product associates with E1/E2 and is detected on the virion surface, albeit at lower stoichiometric levels than other structural proteins [ 5 ]. TF also inhibits type I interferon (IFN) responses in cultured cells and in vivo through a mechanism dependent upon palmitoylation of the protein [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

A molecular understanding of alphavirus entry

et al. 2020

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Alphaviruses cause severe human illnesses including persistent arthritis and fatal encephalitis. As alphavirus entry into target cells is the first step in infection, intensive research efforts have focused on elucidating aspects of this pathway, including attachment, internalization, and fusion. Herein, we review recent developments in the molecular understanding of alphavirus entry both in vitro and in vivo and how these advances might enable the design of therapeutics targeting this critical step in the alphavirus life cycle.

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Section: Introductionmentioning

confidence: 99%

A molecular understanding of alphavirus entry

et al. 2020

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“…[14][15][16] A programmed ribosomal frameshift into the -1 reading frame (-1PRF) occurs with 10-15% efficiency during the translation of the 6K protein and gives rise to a secondary form of the polyprotein. This frameshifted polyprotein contains the TransFrame (TF) protein, 13,17 a known virulence factor, [18][19][20][21] in place of the 6K and E1 proteins ( Figure 1B). Because -1PRF precludes the translation of E1, the efficiency of ribosomal frameshifting (1-48% in alphaviruses) 22 influences the stoichiometric ratio of the E1 and E2 glycoproteins and the net accumulation of spike complexes.…”

Section: Introductionmentioning

confidence: 99%

Cotranslational folding stimulates programmed ribosomal frameshifting in the alphavirus structural polyprotein

Harrington

Zimmer

Chamness

et al. 2020

Journal of Biological Chemistry

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Viruses maximize their genetic coding capacity through a variety of biochemical mechanisms, including programmed ribosomal frameshifting (PRF), which facilitates the production of multiple proteins from a single mRNA transcript. PRF is typically stimulated by structural elements within the mRNA that generate mechanical tension between the transcript and ribosome. However, in this work, we show that the forces generated by the cotranslational folding of the nascent polypeptide chain can also enhance PRF. Using an array of biochemical, cellular, and computational techniques, we first demonstrate that the Sindbis virus structural polyprotein forms two competing topological isomers during its biosynthesis at the ribosome-translocon complex. We then show that the formation of one of these topological isomers is linked to PRF. Coarse-grained molecular dynamics simulations reveal that the translocon-mediated membrane integration of a transmembrane domain upstream from the ribosomal slip site generates a force on the nascent polypeptide chain that scales with observed frameshifting. Together, our results indicate that cotranslational folding of this viral protein generates a tension that stimulates PRF. To our knowledge, this constitutes the first example in which the conformational state of the nascent polypeptide chain has been linked to PRF. These findings raise the possibility that, in addition to RNA-mediated translational recoding, a variety of cotranslational folding or binding events may also stimulate PRF.

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“…Some rely on these motifs to coordinate genomic replication, while others utilize PRF to regulate the production of the structural proteins that mediate assembly (Penn et al, 2020a). In some cases, the frameshift products are themselves virulence factors that antagonize the host interferon response (Hallengard et al, 2014; Rogers et al, 2020; Snyder et al, 2013; Taylor et al, 2016). For these reasons, the efficiency of PRF, which is globally regulated by both host and viral proteins (Napthine et al, 2017; Wang et al, 2019), is often critical for infection and immunity.…”

Section: Introductionmentioning

confidence: 99%

Coordination of -1 Programmed Ribosomal Frameshifting by Transcript and Nascent Chain Features Revealed by Deep Mutational Scanning

et al. 2021

Preprint

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Programmed ribosomal frameshifting (PRF) is a translational recoding mechanism that enables the synthesis of multiple polypeptides from a single transcript. In the alphavirus structural polyprotein, -1PRF is coordinated by a slippery sequence in the transcript, an RNA stem-loop, and a conformational transition in the nascent polypeptide chain. To characterize each of these effectors, we measured the effects of 4,530 mutations on -1PRF by deep mutational scanning. While most mutations within the slip-site and stem-loop disrupt -1PRF, mutagenic effects upstream of the slip-site are far more variable. Molecular dynamics simulations of polyprotein biogenesis suggest many of these mutations alter stimulatory forces on the nascent chain through their effects on translocon-mediated cotranslational folding. Finally, we provide evidence suggesting the coupling between cotranslational folding and -1PRF depends on the translation kinetics upstream of the slip-site. These findings demonstrate how -1PRF is coordinated by features within both the transcript and nascent chain.

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TF protein of Sindbis virus antagonizes host type I interferon responses in a palmitoylation-dependent manner

Cited by 16 publications

References 53 publications

A molecular understanding of alphavirus entry

A molecular understanding of alphavirus entry

Cotranslational folding stimulates programmed ribosomal frameshifting in the alphavirus structural polyprotein

Coordination of -1 Programmed Ribosomal Frameshifting by Transcript and Nascent Chain Features Revealed by Deep Mutational Scanning

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