mRNA structure regulates protein expression through changes in functional half-life

Mauger, David; Cabral, B. Joseph; Presnyak, Vladimir; Su, Stephen; Reid, David W.; Goodman, Brooke; Link, Kristian H.; Khatwani, Nikhil; Reynders, John; Moore, Melissa J.; McFadyen, Iain

doi:10.1073/pnas.1908052116

Cited by 387 publications

(366 citation statements)

References 44 publications

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“…As more sources of structural data continue to be made available in higher quantity, resolution, and scope, the EternaBench and EternaFold frameworks will allow for the usage of these datasets in continually assessing and improving RNA structure prediction. An important use case for EternaFold will be computationally guided design of RNA medicines, including structured mRNAs 19 for viral pandemics like COVID-19.…”

Section: Discussionmentioning

confidence: 99%

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RNA secondary structure packages evaluated and improved by high-throughput experiments

Wayment-Steele

Kladwang

Participants

et al. 2020

Preprint

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The computer-aided study and design of RNA molecules is increasingly prevalent across a range of disciplines, yet little is known about the accuracy of commonly used structure prediction packages in real-world tasks. Here, we evaluate the performance of current packages using EternaBench, a dataset comprising 23 in vitro structure mapping and 11 riboswitch activity datasets involving 18,509 synthetic sequences from the crowdsourced RNA design project Eterna. We find that CONTRAfold and RNAsoft, packages with parameters derived through statistical learning, achieve consistently higher accuracy than more widely used packages like the ViennaRNA software, which derive parameters primarily from thermodynamic experiments.Motivated by these results, we develop a multitask-learning-based model, EternaFold, which demonstrates improved performance that generalizes to diverse external datasets, including complete viral genomes probed in vivo and synthetic designs modeling mRNA vaccines.

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Section: Discussionmentioning

confidence: 99%

“…Cloud Labs (SHAPE-CE, SHAPE-MaP, DMS-MaP-seq vs. MAP-seq) and for distinct molecules, including viral genomes 21, 35-40 ribosomal RNAs40,41 , and mRNAs designed to improve protein expression19 (Table 2,…”

mentioning

confidence: 99%

RNA secondary structure packages evaluated and improved by high-throughput experiments

Wayment-Steele

Kladwang

Participants

et al. 2020

Preprint

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“…Producing cell lines and clinical grade subunit protein typically takes more than 1 year, while manufacturing nucleic acid vaccines can be done in a matter of weeks 16,17 . In addition to advantages in manufacturing speed, mRNA vaccines are potently immunogenic and elicit both humoral and cellular immunity 18–20 . Therefore, we evaluated mRNA formulated in lipid nanoparticles (mRNA/LNP) as a delivery vehicle for the MERS S-2P and found that transmembrane-anchored MERS S-2P mRNA elicited better neutralizing antibody responses than secreted MERS S-2P (Extended Data Fig.…”

Section: Figurementioning

confidence: 99%

SARS-CoV-2 mRNA Vaccine Development Enabled by Prototype Pathogen Preparedness

Corbett

Edwards

Leist

et al. 2020

Preprint

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39A SARS-CoV-2 vaccine is needed to control the global COVID-19 public health crisis. Atomic-40 level structures directed the application of prefusion-stabilizing mutations that improved 41 expression and immunogenicity of betacoronavirus spike proteins. Using this established 42 immunogen design, the release of SARS-CoV-2 sequences triggered immediate rapid 43 manufacturing of an mRNA vaccine expressing the prefusion-stabilized SARS-CoV-2 spike 44 trimer (mRNA-1273). Here, we show that mRNA-1273 induces both potent neutralizing antibody 45 and CD8 T cell responses and protects against SARS-CoV-2 infection in lungs and noses of 46 mice without evidence of immunopathology. mRNA-1273 is currently in a Phase 2 clinical trial 47 sequences (then known as "2019-nCoV") on January 10 th , the 2P mutations were substituted 98 into S positions aa986 and 987 to produce prefusion-stabilized SARS-CoV-2 S (S-2P) protein 99 for structural analysis 22 and serological assay development 23,24 in silico without additional 100 experimental validation. Within 5 days of sequence release, current Good Manufacturing 101

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“…mRNA levels don't always correspond to protein levels due to various factors, including post-transcriptional modification, mRNA stability, and regulation by miRNAs (Valencia-Sanchez et al, 2006;Nachtergaele and He, 2017;Nouaille et al, 2017;Mauger et al, 2019). Therefore, measuring protein levels during infection can provide a more direct functional relationship between the virus and the host (Koussounadis et al, 2015;Liu et al, 2016).…”

Section: Proteomics Studies In Hcmvmentioning

confidence: 99%

Systems Virology and Human Cytomegalovirus: Using High Throughput Approaches to Identify Novel Host-Virus Interactions During Lytic Infection

Lee

Grey

2020

Front. Cell. Infect. Microbiol.

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Human Cytomegalovirus (HCMV) is a highly prevalent herpesvirus, persistently infecting between 30 and 100% of the population, depending on socioeconomic status (Fields et al., 2013). HCMV remains an important clinical pathogen accounting for more than 60% of complications associated with solid organ transplant patients (Kotton, 2013; Kowalsky et al., 2013; Bruminhent and Razonable, 2014). It is also the leading cause of infectious congenital birth defects and has been linked to chronic inflammation and immune aging (Ballard et al., 1979; Griffith et al., 2016; Jergovic et al., 2019). There is currently no effective vaccine and HCMV antivirals have significant side effects. As current antivirals target viral genes, the virus can develop resistance, reducing drug efficacy. There is therefore an urgent need for new antiviral agents that are effective against HCMV, have better toxicity profiles and are less vulnerable to the emergence of resistant strains. Targeting of host factors that are critical to virus replication is a potential strategy for the development of novel antivirals that circumvent the development of viral resistance. Systematic high throughput approaches provide powerful methods for the identification of novel host-virus interactions. As well as contributing to our basic understanding of virus and cell biology, such studies provide potential targets for the development of novel antiviral agents. High-throughput studies, such as RNA sequencing, proteomics, and RNA interference screens, are useful tools to identify HCMV-induced global changes in host mRNA and protein expression levels and host factors important for virus replication. Here, we summarize new findings on HCMV lytic infection from high-throughput studies since 2014 and how screening approaches have evolved.

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mRNA structure regulates protein expression through changes in functional half-life

Cited by 387 publications

References 44 publications

RNA secondary structure packages evaluated and improved by high-throughput experiments

RNA secondary structure packages evaluated and improved by high-throughput experiments

SARS-CoV-2 mRNA Vaccine Development Enabled by Prototype Pathogen Preparedness

Systems Virology and Human Cytomegalovirus: Using High Throughput Approaches to Identify Novel Host-Virus Interactions During Lytic Infection

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