Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis

Shah, Priya S.; Link, Nichole; Jang, Gwendolyn Μ.; Sharp, Phillip P.; Zhu, Tongtong; Swaney, Danielle L.; Johnson, Jeffrey R.; Dollen, John Von; Ramage, Holly; Satkamp, Laura; Newton, Billy W.; Hüttenhain, Ruth; Petit, Marine J.; Baum, Tierney; Everitt, Amanda; Laufman, Orly; Tassetto, Michel; Shales, Michael; Stevenson, Erica; Iglesias, Gabriel N.; Shokat, L.; Tripathi, Shashank; Balasubramaniam, Vinod; Webb, Laurence G.; Aguirre, Sebastián; Willsey, A. Jeremy; Garcı́a-Sastre, Adolfo; Pollard, Katherine S.; Cherry, Sara; Gamarnik, Andrea V.; Marazzi, Ivan; Taunton, Jack; Fernández-Sesma, Ana; Bellen, Hugo J.; Andino, Raul; Krogan, Nevan J.

doi:10.1016/j.cell.2018.11.028

Cited by 272 publications

(399 citation statements)

References 81 publications

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“…To test whether pharmacological inhibition of the Sec61 translocon complex phenocopies the genetic knockdown, we treated cells with SEC61 inhibitors, CT8 (22) and PS3061 (24). We observed that treatment of MM cell lines with increasing concentrations of these compounds results in an up to five-fold dose-dependent increase in cell-surface BCMA levels and a decrease in cell surface CD38 levels, as evidenced by flow cytometry (Figs.…”

Section: The Sec61 Translocon Regulates Bcma Protein Levelsmentioning

confidence: 97%

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

Ramkumar

Abarientos

Tian

et al. 2019

Preprint

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Cancer cells commonly develop resistance to immunotherapy by loss of antigen expression. Combinatorial treatments that increase levels of the target antigen on the surface of cancer cells have the potential to restore efficacy to immunotherapy. Here, we use our CRISPR interference and CRISPR activation-based functional genomics platform to systematically identify pathways controlling cell-surface expression of the multiple myeloma immunotherapy antigen - B cell maturation antigen, BCMA. We discovered that pharmacological inhibition of HDAC7 and the Sec61 complex increased cell-surface BCMA, including in primary patient cells. Importantly, pharmacological Sec61 inhibition enhanced the anti-myeloma efficacy of a BCMA-targeted antibody-drug conjugate. A CRISPR interference CAR-T coculture screen enabled us to identify both antigen-dependent and -independent mechanisms controlling response of myeloma cells to BCMA-targeted CAR-T cells. Thus, our study demonstrates the potential of CRISPR screens to uncover mechanisms controlling response of cancer cells to immunotherapy and to suggest potential combination therapies.Key PointsUsing CRISPR screens, we systematically identify mechanisms increasing expression of the immunotherapy target BCMA and ADC efficacy.We also identify antigen-independent mechanisms regulating response of cancer cells to BCMA-CAR-T cells.

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Section: The Sec61 Translocon Regulates Bcma Protein Levelsmentioning

confidence: 97%

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

Ramkumar

Abarientos

Tian

et al. 2019

Preprint

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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

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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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“…In addition to its role in STAT2 degradation, DENV NS5 protein is also able to interfere with ISG expression. First, both DENV and ZIKV NS5 selectively inhibit ISG expression by binding to and antagonizing the transcription factor PAF1C [125]. Second, DENV NS5 hijacks core components of the spliceosomal machinery, namely CD2BP2 and DDX23, resulting in an alteration of isoform abundance and stoichiometry of many antiviral factors such as RIG-I, ISG15, or IL-8, hence contributing to an environment favourable to viral replication [126].…”

Section: Interference With Other Mechanismsmentioning

confidence: 99%

“…This shows that sfRNA plays two distinct roles, albeit using the same cellular factors, in the evasion of the innate immune response in mammalian hosts or arthropod vectors. This concept of different roles of host factors between the mammalian hosts or arthropod vectors will most likely be explored in depth in the future considering that a recent system biology study identified more than 45 shared pathway interactions between DENV-human and DENV-mosquito interactomes in the context of innate immune evasion and viral pathogenesis [125].…”

Section: Interference With Other Mechanismsmentioning

confidence: 99%

The Interplay between Dengue Virus and the Human Innate Immune System: A Game of Hide and Seek

et al. 2019

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With 40% of the world population at risk, infections with dengue virus (DENV) constitute a serious threat to public health. While there is no antiviral therapy available against this potentially lethal disease, the efficacy of the only approved vaccine is not optimal and its safety has been recently questioned. In order to develop better vaccines based on attenuated and/or chimeric viruses, one must consider how the human immune system is engaged during DENV infection. The activation of the innate immunity through the detection of viruses by cellular sensors is the first line of defence against those pathogens. This triggers a cascade of events which establishes an antiviral state at the cell level and leads to a global immunological response. However, DENV has evolved to interfere with the innate immune signalling at multiple levels, hence dampening antiviral responses and favouring viral replication and dissemination. This review elaborates on the interplay between DENV and the innate immune system. A special focus is given on the viral countermeasure mechanisms reported over the last decade which should be taken into consideration during vaccine development.Vaccines 2019, 7, 145 2 of 21 serotypes (1-4) in one given restricted geographic area [4,5]. While there is an unmet medical need regarding strategies against dengue, the incidence of this disease is expected to geographically expand in the future considering that the arthropod vector is colonizing northern European and American territories with temperate climates. Clinical ManifestationDENV infection is characterized by a mixed clinical presentation that ranges from an asymptomatic disease to a mild febrile prodrome all the way to a severe hemorrhagic fever and shock syndrome. All infected individuals, asymptomatic or not, can transmit DENV to Aedes mosquitoes during a blood meal, making it difficult to precisely estimate the actual size of the reservoir at any given time. DENV infection severity is classified according to the World Health Organization (WHO) 1997 and 2009 guidelines [6]. Dengue "without warning signs" (or dengue fever) regroups at-risk individuals with fever and at least two of the following signs and symptoms: nausea/vomiting, rash, headaches, eye pain, muscle aches, joint pain, leukopenia, or positivity at the tourniquet test. Dengue "with warning signs of severe infection" (or dengue hemorrhagic fever) includes in addition to the previous signs and symptoms abdominal pain, persistent vomiting, ascites, pleural effusion, mucosal bleeding, lethargy or restlessness, hepatomegaly, and an increase in hematocrit paired with rapid decrease in platelet count. Lastly, severe dengue (or dengue shock) occurs when the infection leads to severe plasma leakage, massive bleeding, and multiple organ failures. As of now, the therapeutic arsenal against DENV infection is fairly limited and only consists of supportive care and intravenous fluid therapy.From a host-pathogen interaction point of view, it is interesting to note that, in the majority of DENV-...

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Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis

Cited by 272 publications

References 81 publications

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

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

The Interplay between Dengue Virus and the Human Innate Immune System: A Game of Hide and Seek

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