scholarly journals Complement pathway amplifies caspase-11–dependent cell death and endotoxin-induced sepsis severity

2016 ◽  
Vol 213 (11) ◽  
pp. 2365-2382 ◽  
Author(s):  
Brooke A. Napier ◽  
Sky W. Brubaker ◽  
Timothy E. Sweeney ◽  
Patrick Monette ◽  
Greggory H. Rothmeier ◽  
...  
Keyword(s):  
Cell Death ◽  
Cleavage Product ◽  
Innate Immune ◽  
Sepsis Severity ◽  
Human Sepsis ◽  
Proinflammatory Mediators ◽  
Mapk Activity ◽  
Innate Immune Signaling ◽  
Genome Wide ◽  
Dependent Cell

Cell death and release of proinflammatory mediators contribute to mortality during sepsis. Specifically, caspase-11–dependent cell death contributes to pathology and decreases in survival time in sepsis models. Priming of the host cell, through TLR4 and interferon receptors, induces caspase-11 expression, and cytosolic LPS directly stimulates caspase-11 activation, promoting the release of proinflammatory cytokines through pyroptosis and caspase-1 activation. Using a CRISPR-Cas9–mediated genome-wide screen, we identified novel mediators of caspase-11–dependent cell death. We found a complement-related peptidase, carboxypeptidase B1 (Cpb1), to be required for caspase-11 gene expression and subsequent caspase-11–dependent cell death. Cpb1 modifies a cleavage product of C3, which binds to and activates C3aR, and then modulates innate immune signaling. We find the Cpb1–C3–C3aR pathway induces caspase-11 expression through amplification of MAPK activity downstream of TLR4 and Ifnar activation, and mediates severity of LPS-induced sepsis (endotoxemia) and disease outcome in mice. We show C3aR is required for up-regulation of caspase-11 orthologues, caspase-4 and -5, in primary human macrophages during inflammation and that c3aR1 and caspase-5 transcripts are highly expressed in patients with severe sepsis; thus, suggesting that these pathways are important in human sepsis. Our results highlight a novel role for complement and the Cpb1–C3–C3aR pathway in proinflammatory signaling, caspase-11 cell death, and sepsis severity.

Genome-wide RNAi screening implicates the E3 ubiquitin ligase Sherpa in mediating innate immune signaling by Toll inDrosophilaadults

2015 ◽  
Vol 8 (400) ◽  
pp. ra107-ra107 ◽  
Author(s):  
Hirotaka Kanoh ◽  
Li-Li Tong ◽  
Takayuki Kuraishi ◽  
Yamato Suda ◽  
Yoshiki Momiuchi ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Innate Immune ◽  
Immune Signaling ◽  
Rnai Screening ◽  
Innate Immune Signaling ◽  
Genome Wide

scholarly journals A genome-wide RNAi screen reveals multiple regulators of caspase activation

2007 ◽  
Vol 179 (4) ◽  
pp. 619-626 ◽  
Author(s):  
Caroline H. Yi ◽  
Dodzie K. Sogah ◽  
Michael Boyce ◽  
Alexei Degterev ◽  
Dana E. Christofferson ◽  
...  
Keyword(s):  
Cell Death ◽  
Mammalian Cells ◽  
Caspase Activation ◽  
Functional Conservation ◽  
Cellular Processes ◽  
Regulatory Circuits ◽  
Genome Wide ◽  
A Genome ◽  
Dependent Cell ◽  
Functionally Diverse

Apoptosis is an evolutionally conserved cellular suicide mechanism that can be activated in response to a variety of stressful stimuli. Increasing evidence suggests that apoptotic regulation relies on specialized cell death signaling pathways and also integrates diverse signals from additional regulatory circuits, including those of cellular homeostasis. We present a genome-wide RNA interference screen to systematically identify regulators of apoptosis induced by DNA damage in Drosophila melanogaster cells. We identify 47 double- stranded RNA that target a functionally diverse set of genes, including several with a known function in promoting cell death. Further characterization uncovers 10 genes that influence caspase activation upon the removal of Drosophila inhibitor of apoptosis 1. This set includes the Drosophila initiator caspase Dronc and, surprisingly, several metabolic regulators, a candidate tumor suppressor, Charlatan, and an N-acetyltransferase, ARD1. Importantly, several of these genes show functional conservation in regulating apoptosis in mammalian cells. Our data suggest a previously unappreciated fundamental connection between various cellular processes and caspase-dependent cell death.

scholarly journals Mitochondrial Modulations, Autophagy Pathways Shifts in Viral Infections: Consequences of COVID-19

2021 ◽  
Vol 22 (15) ◽  
pp. 8180
Author(s):  
Shailendra Pratap Singh ◽  
Salomon Amar ◽  
Pinky Gehlot ◽  
Sanjib K. Patra ◽  
Navjot Kanwar ◽  
...  
Keyword(s):  
Cell Death ◽  
Essential Role ◽  
Viral Infections ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Innate Immune ◽  
Innate Immune Signaling ◽  
Promising Target ◽  
Intracellular Organelles ◽  
Viral Proliferation

Mitochondria are vital intracellular organelles that play an important role in regulating various intracellular events such as metabolism, bioenergetics, cell death (apoptosis), and innate immune signaling. Mitochondrial fission, fusion, and membrane potential play a central role in maintaining mitochondrial dynamics and the overall shape of mitochondria. Viruses change the dynamics of the mitochondria by altering the mitochondrial processes/functions, such as autophagy, mitophagy, and enzymes involved in metabolism. In addition, viruses decrease the supply of energy to the mitochondria in the form of ATP, causing viruses to create cellular stress by generating ROS in mitochondria to instigate viral proliferation, a process which causes both intra- and extra-mitochondrial damage. SARS-COV2 propagates through altering or changing various pathways, such as autophagy, UPR stress, MPTP and NLRP3 inflammasome. Thus, these pathways act as potential targets for viruses to facilitate their proliferation. Autophagy plays an essential role in SARS-COV2-mediated COVID-19 and modulates autophagy by using various drugs that act on potential targets of the virus to inhibit and treat viral infection. Modulated autophagy inhibits coronavirus replication; thus, it becomes a promising target for anti-coronaviral therapy. This review gives immense knowledge about the infections, mitochondrial modulations, and therapeutic targets of viruses.

scholarly journals Genome-wide CRISPR-Cas9 screen reveals the importance of the heparan sulfate pathway and the conserved oligomeric golgi complex for synthetic dsRNA uptake and Sindbis virus infection

2020 ◽  
Author(s):  
Olivier Petitjean ◽  
Erika Girardi ◽  
Richard Patryk Ngondo ◽  
Vladimir Lupashin ◽  
Sébastien Pfeffer
Keyword(s):  
Cell Death ◽  
Heparan Sulfate ◽  
Cell Survival ◽  
Sindbis Virus ◽  
Human Cells ◽  
Innate Immune ◽  
Genome Wide ◽  
A Genome ◽  
Conserved Oligomeric Golgi Complex ◽  
Conserved Oligomeric Golgi

AbstractDouble stranded RNA (dsRNA) is the hallmark of many viral infections. dsRNA is produced either by RNA viruses during replication or by DNA viruses upon convergent transcription. Synthetic dsRNA is also able to mimic viral-induced activation of innate immune response and cell death. In this study, we employed a genome-wide CRISPR-Cas9 loss of function screen based on cell survival in order to identify genes implicated in the host response to dsRNA. By challenging HCT116 human cells with either synthetic dsRNA or Sindbis virus (SINV), we identified the heparan sulfate (HS) pathway as a crucial factor for dsRNA entry and we validated SINV dependency on HS. Interestingly, we uncovered a novel role for COG4, a component of the Conserved Oligomeric Golgi (COG) complex, as a factor involved in cell survival to both dsRNA and SINV in human cells. We showed that COG4 knock-out led to a decrease of extracellular HS, specifically affected dsRNA transfection efficiency and reduced viral production, explaining the increased cell survival of these mutants.ImportanceWhen facing a viral infection, the organism has to put in place a number of defense mechanisms in order to clear the pathogen from the cell. At the early phase of this preparation for fighting against the invader, the innate immune response is triggered by the sensing of danger signals. Among those molecular cues, double-stranded (dsRNA) is a very potent inducer of different reactions at the cellular level that can ultimately lead to cell death. Using a genome-wide screening approach, we set to identify genes involved in dsRNA entry, sensing and apoptosis induction in human cells. This allowed us to determine that the heparan sulfate pathway and the Conserved Oligomeric Golgi complex are key determinants allowing entry of both dsRNA and viral nucleic acid leading to cell death.

scholarly journals Reovirus σ3 Protein Limits Interferon Expression and Cell Death Induction

2020 ◽  
Vol 94 (22) ◽  
Author(s):  
Katherine E. Roebke ◽  
Yingying Guo ◽  
John S. L. Parker ◽  
Pranav Danthi
Keyword(s):  
Cell Death ◽  
Capsid Protein ◽  
Rna Synthesis ◽  
Innate Immune ◽  
Type I ◽  
Outer Capsid Protein ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Dsrna Binding ◽  
Outer Capsid

ABSTRACT Induction of necroptosis by mammalian reovirus requires both type I interferon (IFN)-signaling and viral replication events that lead to production of progeny genomic double-stranded RNA (dsRNA). The reovirus outer capsid protein μ1 negatively regulates reovirus-induced necroptosis by limiting RNA synthesis. To determine if the outer capsid protein σ3, which interacts with μ1, also functions in regulating necroptosis, we used small interfering RNA (siRNA)-mediated knockdown. Similarly to what was observed in diminishment of μ1 expression, knockdown of newly synthesized σ3 enhances necroptosis. Knockdown of σ3 does not impact reovirus RNA synthesis. Instead, this increase in necroptosis following σ3 knockdown is accompanied by an increase in IFN production. Furthermore, ectopic expression of σ3 is sufficient to block IFN expression following infection. Surprisingly, the capacity of σ3 protein to bind dsRNA does not impact its capacity to diminish production of IFN. Consistent with this, infection with a virus harboring a mutation in the dsRNA binding domain of σ3 does not result in enhanced production of IFN or necroptosis. Together, these data suggest that σ3 limits the production of IFN to control innate immune signaling and necroptosis following infection through a mechanism that is independent of its dsRNA binding capacity. IMPORTANCE We use mammalian reovirus as a model to study how virus infection modulates innate immune signaling and cell death induction. Here, we sought to determine how viral factors regulate these processes. Our work highlights a previously unknown role for the reovirus outer capsid protein σ3 in limiting the induction of a necrotic form of cell death called necroptosis. Induction of cell death by necroptosis requires production of interferon. The σ3 protein limits the induction of necroptosis by preventing excessive production of interferon following infection.

scholarly journals Reovirus σ3 protein limits interferon expression and cell death induction

2020 ◽  
Author(s):  
Katherine E Roebke ◽  
Yingying Guo ◽  
John S. L. Parker ◽  
Pranav Danthi
Keyword(s):  
Cell Death ◽  
Capsid Protein ◽  
Rna Synthesis ◽  
Innate Immune ◽  
Type I ◽  
Outer Capsid Protein ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Dsrna Binding ◽  
Outer Capsid

ABSTRACTInduction of necroptosis by mammalian reovirus requires both type I interferon (IFN)-signaling and viral replication events that lead to production of progeny genomic dsRNA. The reovirus outer capsid protein µ1 negatively regulates reovirus-induced necroptosis by limiting RNA synthesis. To determine if the outer capsid protein σ3, which interacts with µ1, also functions in regulating cell death, we used siRNA-mediated knockdown. Similar to that observed by diminishment of µ1 expression, knockdown of newly synthesized σ3 enhances necroptosis. σ3 knockdown does not impact reovirus RNA synthesis. Instead, this increase in necroptosis following σ3 knockdown is accompanied by an increase in IFN production. Furthermore, ectopic expression of σ3 is sufficient to block IFN expression following infection. Surprisingly, the capacity of σ3 protein to bind dsRNA does not impact its capacity to diminish production of IFN. Consistent with this, infection with a virus harboring a mutation in the dsRNA binding domain of σ3 does not result in enhanced production of IFN or cell death. Together, these data suggest that σ3 limits the production of IFN to control innate immune signaling and cell death following infection through a mechanism that is independent of its dsRNA binding capacity.IMPORTANCEWe use mammalian reovirus as a model to study how virus infection modulates innate immune signaling and cell death induction. Here we sought to determine how viral factors regulate these processes. Our work highlights a previously unknown role for the reovirus outer capsid protein σ3 in limiting the induction of a necrotic form of cell death called necroptosis. Induction of cell death by necroptosis requires production of interferon. σ3 limits the induction of necroptosis by preventing excessive production of interferon following infection.

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