Tinkering with Translation: Protein Synthesis in Virus-Infected Cells

Walsh, Derek; Mathews, Michael B.; Mohr, Ian

doi:10.1101/cshperspect.a012351

Cited by 227 publications

(261 citation statements)

References 320 publications

(302 reference statements)

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“…32 DAP5-C induced nonspecific, cap-independent translation of Bcl-2, p53 and CVB3 likely through competition with eIF4E for MAP kinase signal-integrating kinase 1 (MNK1) phosphorylation, thus inhibiting eIF4E from participating in translation initiation. [33][34][35] Changes in function may be explained based on the structural differences in each DAP5 fragment. DAP5 shares structural homology with the middle region of eIF4GI, termed the MIF4G domain.…”

Section: Discussionmentioning

confidence: 99%

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Cleavage of DAP5 by coxsackievirus B3 2A protease facilitates viral replication and enhances apoptosis by altering translation of IRES-containing genes

Hanson

Qiu

et al. 2015

Cell Death Differ

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Cleavage of eukaryotic translation initiation factor 4G (eIF4G) by enterovirus proteases during infection leads to the shutoff of cellular cap-dependent translation, but does not affect the initiation of cap-independent translation of mRNAs containing an internal ribosome entry site (IRES). Death-associated protein 5 (DAP5), a structural homolog of eIF4G, is a translation initiation factor specific for IRES-containing mRNAs. Coxsackievirus B3 (CVB3) is a positive single-stranded RNA virus and a primary causal agent of human myocarditis. Its RNA genome harbors an IRES within the 5′-untranslated region and is translated by a cap-independent, IRES-driven mechanism. Previously, we have shown that DAP5 is cleaved during CVB3 infection. However, the protease responsible for cleavage, cleavage site and effects on the translation of target genes during CVB3 infection have not been investigated. In the present study, we demonstrated that viral protease 2A but not 3C is responsible for DAP5 cleavage, generating 45-and 52-kDa N-(DAP5-N) and C-terminal (DAP5-C) fragments, respectively. By site-directed mutagenesis, we found that DAP5 is cleaved at amino acid G434. Upon cleavage, DAP5-N largely translocated to the nucleus at the later time points of infection, whereas the DAP5-C largely remained in the cytoplasm. Overexpression of these DAP5 truncates demonstrated that DAP5-N retained the capability of initiating IRES-driven translation of apoptosis-associated p53, but not the prosurvival Bcl-2 (B-cell lymphoma 2) when compared with the full-length DAP5. Similarly, DAP5-N expression promoted CVB3 replication and progeny release; on the other hand, DAP5-C exerted a dominant-negative effect on cap-dependent translation. Taken together, viral protease 2A-mediated cleavage of DAP5 results in the production of two truncates that exert differential effects on protein translation of the IRES-containing genes, leading to enhanced host cell death. Coxsackievirus B3 (CVB3), a primary cause of viral myocarditis, is associated with sudden, unexpected death, 1 dilated cardiomyopathy and heart failure. 2 The CVB3 genome consists of a single open reading frame, which is translated to a polyprotein, and subsequently processed by viral proteases 2A and 3C. Similar to other picornaviruses, the CVB3 genome is linked to a small viral peptide, Vpg, rather than a 7-methyl guanosine cap structure at its 5′ terminus. Thus, CVB3 RNA is translated by a cap-independent mechanism and is driven by an internal ribosome entry site (IRES) harbored in the 5′ untranslated region (5′-UTR). 3,4 Viral proteases actively suppress multiple host cell activities that help the virus evade host defense mechanisms, promote viral replication and promote host cell apoptosis. For example, enterovirus proteases can cleave eukaryotic translation initiation factors 4GI (eIF4GI) 5-7 and eIF4GII. 8,9 Picornavirus proteases have also been reported to cleave other canonical translation initiation factors in the cap-dependent translation initiation complex, such as eIF5B 10 and ...

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Section: Discussionmentioning

confidence: 99%

“…50,51 Notably, both eIF4G and DAP5 interact with MNK1, which phosphorylates eIF4E, using the AA-box motif, when eIF4E is in the pretranslation initiation complex. 35 …”

Section: Discussionmentioning

confidence: 99%

Cleavage of DAP5 by coxsackievirus B3 2A protease facilitates viral replication and enhances apoptosis by altering translation of IRES-containing genes

Hanson

Qiu

et al. 2015

Cell Death Differ

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“…Because studies of viruses have proved highly informative for the understanding of cellular translational regulation, we examined the mechanism of action of ICP27, an essential herpes simplex virus type 1 (HSV-1) protein that is a key regulator of host and viral gene expression (6). ICP27 regulates the translation of a subset of viral mRNAs, including the viral mRNAs encoding VP16 and ICP5 (7,8), via an uncharacterized mechanism.…”

Section: Significancementioning

confidence: 99%

“…(D) Oocytes expressing MS2 or MS2-ICP27 were injected with ApG-Luc-MS2 3 (L) or ApG-Luc-ΔMS2 (LΔ) (Fig. S2A, [2] and [6]). PABP was immunoprecipitated (P) from lysates [control: nonspecific rabbit IgG (c)] and detected by immunoblotting (input is 27%).…”

Section: Significancementioning

confidence: 99%

Viral and cellular mRNA-specific activators harness PABP and eIF4G to promote translation initiation downstream of cap binding

Smith

Anderson

Larralde

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Regulation of mRNA translation is a major control point for gene expression and is critical for life. Of central importance is the complex between cap-bound eukaryotic initiation factor 4E (eIF4E), eIF4G, and poly(A) tail-binding protein (PABP) that circularizes mRNAs, promoting translation and stability. This complex is often targeted to regulate overall translation rates, and also by mRNA-specific translational repressors. However, the mechanisms of mRNA-specific translational activation by RNA-binding proteins remain poorly understood. Here, we address this deficit, focusing on a herpes simplex virus-1 protein, ICP27. We reveal a direct interaction with PABP that is sufficient to promote PABP recruitment and necessary for ICP27-mediated activation. PABP binds several translation factors but is primarily considered to activate translation initiation as part of the PABP-eIF4G-eIF4E complex that stimulates the initial cap-binding step. Importantly, we find that ICP27-PABP forms a complex with, and requires the activity of, eIF4G. Surprisingly, ICP27-PABP-eIF4G complexes act independently of the effects of PABP-eIF4G on cap binding to promote small ribosomal subunit recruitment. Moreover, we find that a cellular mRNA-specific regulator, Deleted in Azoospermia-like (Dazl), also employs the PABP-eIF4G interaction in a similar manner. We propose a mechanism whereby diverse RNA-binding proteins directly recruit PABP, in a non-poly(A) tail-dependent manner, to stimulate the small subunit recruitment step. This strategy may be particularly relevant to biological conditions associated with hypoadenylated mRNAs (e.g., germ cells/neurons) and/or limiting cytoplasmic PABP (e.g., viral infection, cell stress). This mechanism adds significant insight into our knowledge of mRNA-specific translational activation and the function of the PABP-eIF4G complex in translation initiation.D espite the importance of translational control, the mechanisms by which specific subsets of mRNAs are translationally regulated are only well defined in a handful of cases. Nevertheless, it is clear that regulation is most often mediated by factors recruited to the 3′ untranslated region (UTR) of mRNAs and frequently occurs at the level of initiation (1). Initiation is a multistep process involving several mRNA-dependent steps, each of which requires eukaryotic initiation factors (eIFs) (2). Initially, the m 7 GpppX cap is bound by eIF4F, comprising a large scaffold protein, eIF4G, bound to the cap-binding protein, eIF4E, and an RNA helicase, eIF4A. The small (40S) ribosomal subunit, initiator tRNA, and associated initiation factors are then recruited as a 43S preinitiation complex. Recruitment is facilitated by eIF4A-dependent removal of RNA secondary structure and by the interaction of 40S-associated eIF3 with eIF4G. The 43S small ribosomal subunit complex then scans the 5′ UTR to locate a start codon, recognition of which promotes release of initiation factors and joining of the large (60S) ribosomal subunit to form an 80S ribosome. Like the cap,...

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“…Viral and bacterial infection are significant stresses that affect many signaling pathways in plants, including TOR signaling-a significant target during viral infection in both mammals and plants (Walsh et al, 2013). TOR-deficient plants appear to be more resistant to both viral and bacterial infection (Schepetilnikov et al, 2011;Ouibrahim et al, 2015;Popa et al, 2016;Zvereva et al, 2016;Meteignier et al, 2017).…”

Section: Tor Signaling Under Biotic Stressmentioning

confidence: 99%

Recent Discoveries on the Role of TOR (Target of Rapamycin) Signaling in Translation in Plants

2017

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Protein synthesis is an intricate, energy-demanding, and tightly controlled process that plays a fundamental role in cell growth, proliferation, and differentiation. The target of rapamycin (TOR) protein kinase integrates stress-, nutrient-, and energy-related signals to optimize protein synthesis outputs. In mammals, TOR is a main controller of capped mRNA translation; how TOR participates in translation initiation in plants is unclear, but active TOR is required for regulation of translation of mRNA with 59-untranslated region (59-UTR) upstream open reading frames (uORFs)-known translation regulatory elements in eukaryotes. Recent data implicates diverse signals such as stress, hormones, and metabolites in regulation of TOR signal transduction pathways and, thus, in response to environmental stress. Here, we review current knowledge of plant TOR complex composition and activation, and its function in translation, compiling data on downstream processes that are under stringent control of TOR in mammals but not yet investigated in plants.Plants have evolved various adaptation mechanisms to ensure their optimal growth, with plant development and behavior being strongly responsive to various external and internal stimuli. By monitoring their environment, plants trigger signal transduction cascades in order to regulate downstream cellular processes, mainly via protein synthesis-a major energy-consuming process (Buttgereit and Brand, 1995). The TOR protein kinase integrates extracellular signals (hormones, biotic and abiotic stresses, growth factors) together with intracellular nutrient availability and energy status to control protein synthesis and other anabolic processes if conditions are favorable, and represses catabolic processes such as autophagy (Albert and Hall, 2015). The past 10 years has boosted research on plant TOR complex composition, highlighted TOR upstream signals and downstream targets, and revealed an interplay between TOR signaling and hormonal, stress, and other pathways in photosynthetic organisms. We are beginning to understand how TOR is activated, and how it controls many cellular processes, such as transcription, translation, and autophagy. Here, we give an overview of recent results on the role of TOR in plant translation control and draw the reader's attention to future questions to address. In plants, inactivation of TOR correlates with a decrease in total polysomal levels (Deprost et al., 2007;Schepetilnikov et al., 2011Schepetilnikov et al., , 2013, strongly suggesting a role for TOR in plant translation. Although a role for TOR in global translation in plants has been documented, the players and mechanisms used to influence different steps of translation initiation -the step most controlled by TOR in mammals-are only starting to emerge. Here, we summarize the current state of knowledge of specific plant translation initiation mechanisms that are controlled by 59-UTR elements of mRNAs and discuss regulation of these mechanisms by TOR/S6 kinase 1 (S6K1) signaling. Examples where TOR re...

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Tinkering with Translation: Protein Synthesis in Virus-Infected Cells

Cited by 227 publications

References 320 publications

Cleavage of DAP5 by coxsackievirus B3 2A protease facilitates viral replication and enhances apoptosis by altering translation of IRES-containing genes

Cleavage of DAP5 by coxsackievirus B3 2A protease facilitates viral replication and enhances apoptosis by altering translation of IRES-containing genes

Viral and cellular mRNA-specific activators harness PABP and eIF4G to promote translation initiation downstream of cap binding

Recent Discoveries on the Role of TOR (Target of Rapamycin) Signaling in Translation in Plants

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