Ribosome Profiling as a Tool to Decipher Viral Complexity

Stern-Ginossar, Noam; Ingolia, Nicholas T.

doi:10.1146/annurev-virology-100114-054854

Cited by 28 publications

(19 citation statements)

References 88 publications

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“…Our current study demonstrates that the two protein isoforms of pUL138 may have both overlapping and distinct functions during HCMV infection. In recent years, many studies have contributed to a body of work that begins to effectively demonstrate the power and function of increased coding capacity in HCMV through transcriptional, translational, and posttranslational mechanisms (9,15,32,33,37,58,59). Further, many examples of viral protein isoforms that have similar or unique functions exist (60)(61)(62)(63)(64)(65)(66)(67), but these examples likely only begin to scratch the surface of the important roles that protein isoforms play in viral infection and virus-host interactions.…”

Section: Identified Cd8mentioning

confidence: 99%

See 1 more Smart Citation

Long and Short Isoforms of the Human Cytomegalovirus UL138 Protein Silence IE Transcription and Promote Latency

Lee

Caviness

Albright

et al. 2016

J Virol

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The UL133-138 locus present in clinical strains of human cytomegalovirus (HCMV) encodes proteins required for latency and reactivation in CD34؉ hematopoietic progenitor cells and virion maturation in endothelial cells. The encoded proteins form multiple homo-and hetero-interactions and localize within secretory membranes. One of these genes, UL136 gene, is expressed as at least five different protein isoforms with overlapping and unique functions. Here we show that another gene from this locus, the UL138 gene, also generates more than one protein isoform. A long form of UL138 (pUL138-L) initiates translation from codon 1, possesses an amino-terminal signal sequence, and is a type one integral membrane protein. Here we identify a short protein isoform (pUL138-S) initiating from codon 16 that displays a subcellular localization similar to that of pUL138-L. Reporter, short-term transcription, and long-term virus production assays revealed that both pUL138-L and pUL138-S are able to suppress major immediate early (IE) gene transcription and the generation of infectious virions in cells in which HCMV latency is studied. The long form appears to be more potent at silencing IE transcription shortly after infection, while the short form seems more potent at restricting progeny virion production at later times, indicating that both isoforms of UL138 likely cooperate to promote HCMV latency. IMPORTANCELatency allows herpesviruses to persist for the lives of their hosts in the face of effective immune control measures for productively infected cells. Controlling latent reservoirs is an attractive antiviral approach complicated by knowledge deficits for how latently infected cells are established, maintained, and reactivated. This is especially true for betaherpesviruses. The functional consequences of HCMV UL138 protein expression during latency include repression of viral IE1 transcription and suppression of virus replication. Here we show that short and long isoforms of UL138 exist and can themselves support latency but may do so in temporally distinct manners. Understanding the complexity of gene expression and its impact on latency is important for considering potential antivirals targeting latent reservoirs. Human cytomegalovirus (HCMV) is a betaherpesvirus that causes birth defects and disease in immunocompromised and immunosuppressed patients and has been associated with cancers, cardiovascular disease, and immune dysfunction (1-3). HCMV productively (lytically) infects differentiated cells, such as fibroblasts, endothelial cells, and epithelial cells, and latently infects incompletely differentiated cells of the myeloid lineage, such as monocytes and CD34 ϩ hematopoietic progenitor cells (HPC) (4, 5). Productive infection in multiple cell types within the human host facilitates viral dissemination, while latency ensures lifelong persistence despite an effective immune response against lyticphase antigens. Periodic reactivations of latent infections into the productive phase perpetuate both lifelong infecti...

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Section: Identified Cd8mentioning

confidence: 99%

“…Estimates of the protein-coding capacity of HCMV have substantially increased with recent studies (32,33) and suggest a complexity in viral protein expression and likely function not previously appreciated. Genomic approaches have also cataloged previously undetected transcribed and translated sequences during both lytic and latent infections (34)(35)(36)(37).…”

mentioning

confidence: 99%

Long and Short Isoforms of the Human Cytomegalovirus UL138 Protein Silence IE Transcription and Promote Latency

Lee

Caviness

Albright

et al. 2016

J Virol

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“…Unlike the multitude of viral translation studies reported in the context of infection [102], and likely complicated due to the significant differences between bacterial and eukaryotic translation, to date, no bacterial translatome-oriented studies in the context of infection have been reported.…”

Section: Secretomics For Identifying Bacterial Extracellular Effectormentioning

confidence: 99%

Omics in Aid of Host-pathogen Interaction Studies: A Bacterial Perspective

Fels¹,

Gevaert²,

Damme³

2017

Preprint

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By providing useful tools to study host-pathogen interactions, next-generation omics has recently enabled the study of gene expression changes in both pathogen and infected host simultaneously. However, since great discriminative power is required to study pathogen and host simultaneously throughout the infection process, the depth of quantitative gene expression profiling has proven to be unsatisfactory when focusing on bacterial pathogens, thus preferentially requiring specific strategies or the development of novel methodologies based on complementary omics approaches. In this review, we focus on the difficulties encountered when making use of omics approaches to study bacterial pathogenesis. Besides, we review different omics strategies (i.e. transcriptomics, proteomics and secretomics) and their applications for studying interactions of pathogens with their host.

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“…Depending on the approach used to arrest ribosomes, the Ribo‐seq technique can capture elongating ribosomes or initiating ribosomes (see Andreev et al., ; Aramayo & Polymenis, ; Bartholomaus, Del Campo, & Ignatova, ; Baudin‐Baillieu, Hatin, Legendre, & Namy, ; Brar & Weissman, ; Calviello & Ohler, ; Gobet & Naef, ; Ingolia, ; Michel & Baranov, ; Mumtaz & Couso, ; Parsons & Myler, ; Stern‐Ginossar, ; Stern‐Ginossar & Ingolia, , for a comprehensive overview of the technique, its applications and limitations). Data tracks for both initiating and elongating ribosomes are hosted on GWIPS‐viz.…”

Section: Introductionmentioning

confidence: 99%

The GWIPS‐viz Browser

Kiniry

Michel

Baranov

2018

CP in Bioinformatics

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GWIPS-viz is a publicly available browser that provides Genome Wide Information on Protein Synthesis through the visualization of ribosome profiling data. Ribosome profiling (Ribo-seq) is a high-throughput technique which isolates fragments of messenger RNA that are protected by the ribosome. The alignment of the ribosome-protected fragments or footprint sequences to the corresponding reference genome and their visualization using GWIPS-viz allows for unique insights into the genome loci that are expressed as potentially translated RNA. The GWIPS-viz browser hosts both Ribo-seq data and corresponding mRNA-seq data from publicly available studies across a number of genomes, avoiding the need for computational processing on the user side. Since its initial publication in 2014, over 1885 tracks have been produced across 24 genomes. This unit describes the navigation of the GWIPS-viz genome browser, the uploading of custom tracks, and the downloading of the Ribo-seq/mRNA-seq alignment data. © 2018 by John Wiley & Sons, Inc.

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Ribosome Profiling as a Tool to Decipher Viral Complexity

Cited by 28 publications

References 88 publications

Long and Short Isoforms of the Human Cytomegalovirus UL138 Protein Silence IE Transcription and Promote Latency

Long and Short Isoforms of the Human Cytomegalovirus UL138 Protein Silence IE Transcription and Promote Latency

Omics in Aid of Host-pathogen Interaction Studies: A Bacterial Perspective

The GWIPS‐viz Browser

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