Type I interferon (IFN) is produced when host sensors detect foreign nucleic acids, but how sensors differentiate self from nonself nucleic acids, such as double-stranded RNA (dsRNA), is incompletely ...understood. Mutations in ADAR1, an adenosine-to-inosine editing enzyme of dsRNA, cause Aicardi-Goutières syndrome, an autoinflammatory disorder associated with spontaneous interferon production and neurologic sequelae. We generated ADAR1 knockout human cells to explore ADAR1 substrates and function. ADAR1 primarily edited Alu elements in RNA polymerase II (pol II)-transcribed mRNAs, but not putative pol III-transcribed Alus. During the IFN response, ADAR1 blocked translational shutdown by inhibiting hyperactivation of PKR, a dsRNA sensor. ADAR1 dsRNA binding and catalytic activities were required to fully prevent endogenous RNA from activating PKR. Remarkably, ADAR1 knockout neuronal progenitor cells exhibited MDA5 (dsRNA sensor)-dependent spontaneous interferon production, PKR activation, and cell death. Thus, human ADAR1 regulates sensing of self versus nonself RNA, allowing pathogen detection while avoiding autoinflammation.
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•ADAR1 edits are found in putative RNA polymerase II (but not III)-derived Alu repeats•ADAR1 prevents translational shutdown during the type I IFN response•ADAR1 dsRNA binding and catalytic activities are required to block PKR activation•ADAR1 KO NPCs exhibit MDA5-dependent IFN production, PKR activation, and cell death
The human RNA-editing enzyme ADAR1 prevents endogenous RNA from activating innate immune sensors (PKR, MDA5), which allows efficient translation during IFN response.
Influenza A virus is an RNA virus that encodes up to 11 proteins and this small coding capacity demands that the virus use the host cellular machinery for many aspects of its life cycle. Knowledge of ...these host cell requirements not only informs us of the molecular pathways exploited by the virus but also provides further targets that could be pursued for antiviral drug development. Here we use an integrative systems approach, based on genome-wide RNA interference screening, to identify 295 cellular cofactors required for early-stage influenza virus replication. Within this group, those involved in kinase-regulated signalling, ubiquitination and phosphatase activity are the most highly enriched, and 181 factors assemble into a highly significant host-pathogen interaction network. Moreover, 219 of the 295 factors were confirmed to be required for efficient wild-type influenza virus growth, and further analysis of a subset of genes showed 23 factors necessary for viral entry, including members of the vacuolar ATPase (vATPase) and COPI-protein families, fibroblast growth factor receptor (FGFR) proteins, and glycogen synthase kinase 3 (GSK3)- . Furthermore, 10 proteins were confirmed to be involved in post-entry steps of influenza virus replication. These include nuclear import components, proteases, and the calcium/calmodulin-dependent protein kinase (CaM kinase) II (CAMK2B). Notably, growth of swine-origin H1N1 influenza virus is also dependent on the identified host factors, and we show that small molecule inhibitors of several factors, including vATPase and CAMK2B, antagonize influenza virus replication.
The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of over one million people worldwide. The causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a ...member of the Coronaviridae family of viruses that can cause respiratory infections of varying severity. The cellular host factors and pathways co-opted during SARS-CoV-2 and related coronavirus life cycles remain ill defined. To address this gap, we performed genome-scale CRISPR knockout screens during infection by SARS-CoV-2 and three seasonal coronaviruses (HCoV-OC43, HCoV-NL63, and HCoV-229E). These screens uncovered host factors and pathways with pan-coronavirus and virus-specific functional roles, including major dependency on glycosaminoglycan biosynthesis, sterol regulatory element-binding protein (SREBP) signaling, bone morphogenetic protein (BMP) signaling, and glycosylphosphatidylinositol biosynthesis, as well as a requirement for several poorly characterized proteins. We identified an absolute requirement for the VMP1, TMEM41, and TMEM64 (VTT) domain-containing protein transmembrane protein 41B (TMEM41B) for infection by SARS-CoV-2 and three seasonal coronaviruses. This human coronavirus host factor compendium represents a rich resource to develop new therapeutic strategies for acute COVID-19 and potential future coronavirus pandemics.
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•Genome-wide CRISPR screens for SARS-CoV-2 and seasonal coronavirus host factors•Identification of host factors and pathways with pan-coronavirus and discrete roles•Coronaviruses co-opt multiple biological pathways•TMEM41B is a critical pan-coronavirus host factor
Schneider et al. conducted parallel genome-wide CRISPR knockout screens with SARS-CoV-2 and three seasonal coronaviruses to identify pan-coronavirus and virus-specific host factor requirements. They identified an interconnected network of host factors required by these four viruses and validated TMEM41B as a pan-coronavirus host factor required for a post-entry step in the coronavirus life cycle.
► We analyze innovation effects of demand-pull/technology-push policies for solar PV. ► We explore domestic and foreign policy effects to investigate innovation spillovers. ► An innovation effect of ...domestic technology-push policies abroad is not detected. ► Yet substantive innovation spillovers of domestic demand-pull policies exist. ► Supranationally coordinated demand-pull policies needed to address spillover issue.
How to foster technical change is a highly relevant and intricate question in the arena of policymaking. Various studies have shown that technology-push and demand-pull policies induce innovation. However, there is a lack of work that distinguishes between the loci of policy support when assessing the policy–innovation relationship. We address this gap by shedding light on the question how the innovation effects of domestic and foreign demand-pull and technology-push policies differ. Using solar photovoltaic modules as a research case we conduct a panel analysis on 15 OECD countries over the period 1978 through 2005 with patent data. Three key findings emerged: First, our analyses find no evidence that domestic technology-push policies foster innovative output outside of national borders. Second, both domestic and foreign demand-pull policies trigger innovative output in a country. Third, we detect no indication that market growth induced by domestic demand-pull policies leads to more national innovative output than market growth induced by foreign demand-pull policies. Consequently, demand-pull policies create significant country-level innovation spillovers, which could disincentivize national policymakers to engage in domestic market creation. Based on these findings we discuss the need to establish supranational demand-pull policy schemes in order to address the spillover issue.
Reactive oxygen species (ROS) are created in cells during oxidative phosphorylation by the respiratory chain in the mitochondria or by the family of NADPH oxidase (NOX) complexes. The first ...discovered and most studied of these complexes, NOX2, mediates the oxidative burst in phagocytes. ROS generated by NOX2 are dreadful weapons: while being essential to kill ingested pathogens they can also cause degenerative changes on tissue if production and release are not balanced by sufficient detoxification. In the last fifteen years evidence has been accumulating that ROS are also integral signaling molecules and are important for regulating autoimmunity and immune-mediated inflammatory diseases. It seems that an accurate redox balance is necessary to sustain an immune state that both prevents the development of overt autoimmunity (the bright side of ROS) and minimizes collateral tissue damage (the dark side of ROS). Herein, we review studies from rodent models of arthritis, lupus, and neurodegenerative diseases that show that low NOX2-derived ROS production is linked to disease and elaborate on the underlying cellular and molecular mechanisms and the translation of these results to disease in humans.
•ROS are created during oxidative phosphorylation and by NADPH oxidase complexes.•ROS-induced signaling regulates immune reactions and can prevent autoimmunity.•Prolonged and uncontrolled ROS production can cause collateral tissue damage.•Temporally and spatial balance of ROS levels is essential to sustain homeostasis.
TMEM41B Is a Pan-flavivirus Host Factor Hoffmann, H.-Heinrich; Schneider, William M.; Rozen-Gagnon, Kathryn ...
Cell,
01/2021, Letnik:
184, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required ...for flavivirus infection, we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results, we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the Flaviviridae family that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of the Coronaviridae also required TMEM41B for infection. Remarkably, single nucleotide polymorphisms present at nearly 20% in East Asian populations reduce flavivirus infection. Based on our mechanistic studies, we propose that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication.
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•TMEM41B is required for flavivirus infection, but autophagy is not required•TMEM41B associates with flavivirus proteins and may facilitate cell membrane remodeling•TMEM41B single nucleotide polymorphisms reduce flavivirus infection•TMEM41B-deficiency confers a heightened innate immune response to flavivirus infection
Hoffmann et al. determine that the transmembrane protein, TMEM41B, is required for infection by members of the Flaviviridae family of viruses. Loss of TMEM41B reduces viral RNA replication and increases innate immune activation in response to flavivirus infection. Thus, TMEM41B is a potential host target for antiviral therapeutics.
Interorganizational relationships are recognized as an increasingly important source of competitive advantage. Hence, goal-oriented management of the alliance portfolio--all the alliances of the ...focal firm--plays a decisive role in company performance. Consequently, the configuration and development of the alliance portfolio become important strategic issues. In light of that, this article develops theoretical propositions that seek to clarify what determines the configuration and evolution of an alliance portfolio, and then presents the results of a longitudinal study to illustrate the developed theoretical framework. Building on contingency theory and a coevolutionary framework, we were able to identify three distinctive types of portfolio strategies at business level and to illustrate how they interact with the development of the business strategy and the business environment. Encompassing all this, the study illustrates and explains developmental paths and patterns in the evolution of an alliance portfolio. The developmental course typically evolves from adapting to shaping and to exploiting (stabilizing), according to the state of strategic uncertainty and the firm's resource endowment. A sudden increase in exogenous strategic uncertainty, however, can lead to a strategic shift back to an exploration or hybrid strategy.
Clinical outcomes of severe acute respiratory syndrome 2 (SARS-CoV-2) infection are highly heterogeneous, ranging from asymptomatic infection to lethal coronavirus disease 2019 (COVID-19). The ...factors underlying this heterogeneity remain insufficiently understood. Genetic association studies have suggested that genetic variants contribute to the heterogeneity of COVID-19 outcomes, but the underlying potential causal mechanisms are insufficiently understood. Here we show that common variants of the apolipoprotein E (APOE) gene, homozygous in approximately 3% of the world's population
and associated with Alzheimer's disease, atherosclerosis and anti-tumour immunity
, affect COVID-19 outcome in a mouse model that recapitulates increased susceptibility conferred by male sex and advanced age. Mice bearing the APOE2 or APOE4 variant exhibited rapid disease progression and poor survival outcomes relative to mice bearing the most prevalent APOE3 allele. APOE2 and APOE4 mice exhibited increased viral loads as well as suppressed adaptive immune responses early after infection. In vitro assays demonstrated increased infection in the presence of APOE2 and APOE4 relative to APOE3, indicating that differential outcomes are mediated by differential effects of APOE variants on both viral infection and antiviral immunity. Consistent with these in vivo findings in mice, our results also show that APOE genotype is associated with survival in patients infected with SARS-CoV-2 in the UK Biobank (candidate variant analysis, P = 2.6 × 10
). Our findings suggest APOE genotype to partially explain the heterogeneity of COVID-19 outcomes and warrant prospective studies to assess APOE genotyping as a means of identifying patients at high risk for adverse outcomes.
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