Enterovirus pathogenesis requires the host methyltransferase SETD3

Diep, Jonathan; Ooi, Yaw Shin; Wilkinson, Alex W.; Peters, Christine; Foy, Eileen; Johnson, Jeffrey R.; Zengel, James; Ding, Siyuan; Weng, Kuo-Feng; Laufman, Orly; Jang, Gwendolyn Μ.; Xu, Jiewei; Young, Tracy A.; Verschueren, Erik; Kobluk, Kristi J.; Elias, Joshua E.; Sarnow, Peter; Greenberg, Harry B.; Hüttenhain, Ruth; Nagamine, Claude M.; Andino, Raul; Krogan, Nevan J.; Gozani, Or; Carette, Jan E.

doi:10.1038/s41564-019-0551-1

Cited by 52 publications

(86 citation statements)

References 61 publications

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“…3). We studied the interacting human proteins in regards to their cell biology, anatomical expression patterns, expression changes during SARS-CoV-2 infection 21 and in relation to other maps of pathogen interacting proteins 19,[22][23][24][25][26][27][28][29][30] (Fig. 2a).…”

Section: Global Analysis Of Sars-cov-2 Host Interacting Proteinsmentioning

confidence: 99%

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

Gordon¹,

Jang²,

Bouhaddou³

et al. 2020

Preprint

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425

586

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ABSTRACTAn outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.

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Section: Global Analysis Of Sars-cov-2 Host Interacting Proteinsmentioning

confidence: 99%

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

Gordon¹,

Jang²,

Bouhaddou³

et al. 2020

Preprint

Self Cite

425

586

View full text Add to dashboard Cite

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“…However, biogenesis of ROs are not essential to the initiation of viral replication since viral replication still occurred in cells when RO formation was delayed (Melia et al, 2017). Another host factor critical for viral RNA replication is the methyltransferase SET domain containing 3 (SETD3) (Diep et al, 2019). The authors showed that the cytosolic form of the actin histadine methyltransferase SETD3 interacts with the viral 2A protease from multiple enteroviral species including EV-D68, EV-A71 and CVA10 and this interaction was important for viral RNA replication (Diep et al, 2019).…”

Section: Host Factors Involved In Enterovirus Entry and Replicationmentioning

confidence: 99%

“…Another host factor critical for viral RNA replication is the methyltransferase SET domain containing 3 (SETD3) (Diep et al, 2019). The authors showed that the cytosolic form of the actin histadine methyltransferase SETD3 interacts with the viral 2A protease from multiple enteroviral species including EV-D68, EV-A71 and CVA10 and this interaction was important for viral RNA replication (Diep et al, 2019). Animals with Setd3 −/− were completely resistant to EV viral infection when injected intracranially or intramuscularly (Diep et al, 2019), supporting the necessity of usurping these mechanisms by EVs within the CNS.…”

Section: Host Factors Involved In Enterovirus Entry and Replicationmentioning

confidence: 99%

Molecular Pathogenicity of Enteroviruses Causing Neurological Disease

Majer¹,

McGreevy

Booth

2020

Front. Microbiol.

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Enteroviruses are single-stranded positive-sense RNA viruses that primarily cause self-limiting gastrointestinal or respiratory illness. In some cases, these viruses can invade the central nervous system, causing life-threatening neurological diseases including encephalitis, meningitis and acute flaccid paralysis (AFP). As we near the global eradication of poliovirus, formerly the major cause of AFP, the number of AFP cases have not diminished implying a non-poliovirus etiology. As the number of enteroviruses linked with neurological disease is expanding, of which many had previously little clinical significance, these viruses are becoming increasingly important to public health. Our current understanding of these non-polio enteroviruses is limited, especially with regards to their neurovirulence. Elucidating the molecular pathogenesis of these viruses is paramount for the development of effective therapeutic strategies. This review summarizes the clinical diseases associated with neurotropic enteroviruses and discusses recent advances in the understanding of viral invasion of the central nervous system, cell tropism and molecular pathogenesis as it correlates with host responses.

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“…CMTR1 is a mRNA methyltransferase and a known regulator of protein expression of IFN-stimulated genes to restrict viral infection 38 . SETD3, also a methyltransferase, is a human host protein critical for infection of a wide range of viruses and participates in viral replication yet its mode of action is currently unknown 39 . The links we identify between CMTR1, SETD3, and RNaseH2 point to potential mechanisms in which CMTR1 and SETD3 interact with RNaseH2 to modulate the innate immune response and affect viral replication.…”

Section: Functional Annotation Of Uncharacterized Proteinsmentioning

confidence: 99%

hu.MAP 2.0: Integration of over 15,000 proteomic experiments builds a global compendium of human multiprotein assemblies

Drew¹,

Wallingford²,

Marcotte³

2020

Preprint

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A general principle of biology is the self-assembly of proteins into functional complexes. Characterizing their composition is, therefore, required for our understanding of cellular functions. Unfortunately, we lack a comprehensive set of protein complexes for human cells. To address this gap, we developed a machine learning framework to identify protein complexes in over 15,000 mass spectrometry experiments which resulted in the identification of nearly 7,000 physical assemblies. We show our resource, hu.MAP 2.0, is more accurate and comprehensive than previous resources and gives rise to many new hypotheses, including for 274 completely uncharacterized proteins. Further, we identify 259 promiscuous proteins that participate in multiple complexes pointing to possible moonlighting roles. We have made hu.MAP 2.0 easily searchable in a web interface (http://humap2.proteincomplexes.org/), which will be a valuable resource for researchers across a broad range of interests including systems biology, structural biology, and molecular explanations of disease.

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Enterovirus pathogenesis requires the host methyltransferase SETD3

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Cited by 52 publications

References 61 publications

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

Molecular Pathogenicity of Enteroviruses Causing Neurological Disease

hu.MAP 2.0: Integration of over 15,000 proteomic experiments builds a global compendium of human multiprotein assemblies

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