DHX15 and Rig-I Coordinate Apoptosis and Innate Immune Signaling by Antiviral RNase L.

During virus infection, the activation of the antiviral endoribonuclease, ribonuclease L (RNase L), by a unique ligand 2'-5'-oilgoadenylate (2-5A) causes the cleavage of single-stranded viral and cellular RNA targets, restricting protein synthesis, activating stress response pathways, and promoting cell death to establish broad antiviral effects. The immunostimulatory dsRNA cleavage products of RNase L activity (RL RNAs) recruit diverse dsRNA sensors to activate signaling pathways to amplify interferon (IFN) production and activate inflammasome, but the sensors that promote cell death are not known. In this study, we found that DEAH-box polypeptide 15 (DHX15) and retinoic acid-inducible gene I (Rig-I) are essential for apoptosis induced by RL RNAs and require mitochondrial antiviral signaling (MAVS), c-Jun amino terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK) for caspase-3-mediated intrinsic apoptosis.

Ribosomal dysregulation: A conserved pathophysiological mechanism in human depression and mouse chronic stress.

The underlying biological mechanisms that contribute to the heterogeneity of major depressive disorder (MDD) presentation remain poorly understood, highlighting the need for a conceptual framework that can explain this variability and bridge the gap between animal models and clinical endpoints. Here, we hypothesize that comparative analysis of molecular data from different experimental systems of chronic stress, and MDD has the potential to provide insight into these mechanisms and address this gap. Thus, we compared transcriptomic profiles of brain tissue from postmortem MDD subjects and from mice exposed to chronic variable stress (CVS) to identify orthologous genes.

Viral Hemorrhagic Septicemia Virus Activates Integrated Stress Response Pathway and Induces Stress Granules to Regulate Virus Replication.

Virus infection activates integrated stress response (ISR) and stress granule (SG) formation and viruses counteract by interfering with SG assembly, suggesting an important role in antiviral defense. The infection of fish cells by Viral Hemorrhagic Septicemia Virus (VHSV), activates the innate immune recognition pathway and the production of type I interferon (IFN). However, the mechanisms by which VHSV interacts with ISR pathway regulating SG formation is poorly understood.

ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections.

Host response to a viral infection includes the production of type I interferon (IFN) and the induction of interferon-stimulated genes that have broad antiviral effects. One of the key antiviral effectors is the IFN-inducible oligoadenylate synthetase/ribonuclease L (OAS/RNase L) pathway, which is activated by double-stranded RNA to synthesize unique oligoadenylates, 2-5A, to activate RNase L. RNase L exerts an antiviral effect by cleaving diverse RNA substrates, limiting viral replication; many viruses have evolved mechanisms to counteract the OAS/RNase L pathway.

Effect of the Viral Hemorrhagic Septicemia Virus Nonvirion Protein on Translation via PERK-eIF2α Pathway.

Viral hemorrhagic septicemia virus (VHSV) is one of the most deadly infectious fish pathogens, posing a serious threat to the aquaculture industry and freshwater ecosystems worldwide. Previous work showed that VHSV sub-genotype IVb suppresses host innate immune responses, but the exact mechanism by which VHSV IVb inhibits antiviral response remains incompletely characterized. As with other novirhabdoviruses, VHSV IVb contains a unique and highly variable nonvirion (NV) gene, which is implicated in viral replication, virus-induced apoptosis and regulating interferon (IFN) production.

RNase L Amplifies Interferon Signaling by Inducing Protein Kinase R-Mediated Antiviral Stress Granules.

Virus infection leads to activation of the interferon (IFN)-induced endoribonuclease RNase L, which results in degradation of viral and cellular RNAs. Both cellular and viral RNA cleavage products of RNase L bind pattern recognition receptors (PRRs), like retinoic acid-inducible I (Rig-I) and melanoma differentiation-associated protein 5 (MDA5), to further amplify IFN production and antiviral response. Although much is known about the mechanics of ligand binding and PRR activation, how cells coordinate RNA sensing with signaling response and interferon production remains unclear.

RNase L Induces Expression of A Novel Serine/Threonine Protein Kinase, DRAK1, to Promote Apoptosis.

Apoptosis of virus-infected cells is an effective antiviral mechanism in addition to interferon induction to establish antiviral state to restrict virus spread. The interferon-inducible 2'-5' oligoadenylate synthetase/RNase L pathway results in activation of RNase L in response to double stranded RNA and cleaves diverse RNA substrates to amplify interferon induction and promote apoptosis. Here we show that RNase L induces expression of Death-associated protein kinase-Related Apoptosis-inducing protein Kinase 1 (DRAK1), a member of the death-associated protein kinase family and interferon-signaling pathway is required for induction.

Role of Viral Hemorrhagic Septicemia Virus Matrix (M) Protein in Suppressing Host Transcription.

Viral hemorrhagic septicemia virus (VHSV) is a pathogenic fish rhabdovirus found in discrete locales throughout the Northern Hemisphere. VHSV infection of fish cells leads to upregulation of the host's virus detection response, but the virus quickly suppresses interferon (IFN) production and antiviral gene expression. By systematically screening each of the six VHSV structural and nonstructural genes, we identified matrix protein (M) as the virus' most potent antihost protein.

RNase L Suppresses Androgen Receptor Signaling, Cell Migration and Matrix Metalloproteinase Activity in Prostate Cancer Cells.

The interferon antiviral pathways and prostate cancer genetics converge on a regulated endoribonuclease, RNase L. Positional cloning and linkage studies mapped Hereditary Prostate Cancer 1 () to . To date, there is no correlation of viral infections with prostate cancer, suggesting that RNase L may play additional roles in tumor suppression.

The Roles of RNase-L in Antimicrobial Immunity and the Cytoskeleton-Associated Innate Response.

The interferon (IFN)-regulated endoribonuclease RNase-L is involved in multiple aspects of the antimicrobial innate immune response. It is the terminal component of an RNA cleavage pathway in which dsRNA induces the production of RNase-L-activating 2-5A by the 2'-5'-oligoadenylate synthetase. The active nuclease then cleaves ssRNAs, both cellular and viral, leading to downregulation of their expression and the generation of small RNAs capable of activating retinoic acid-inducible gene-I (RIG-I)-like receptors or the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome.

RNase L Cleavage Products Promote Switch from Autophagy to Apoptosis by Caspase-Mediated Cleavage of Beclin-1.

Autophagy and apoptosis share regulatory molecules enabling crosstalk in pathways that affect cellular homeostasis including response to viral infections and survival of tumor cells. Ribonuclease L (RNase L) is an antiviral endonuclease that is activated in virus-infected cells and cleaves viral and cellular single-stranded RNAs to produce small double-stranded RNAs with roles in amplifying host responses. Activation of RNase L induces autophagy and apoptosis in many cell types.

Modulatory effects by neodymium-doped yttrium aluminum garnet laser on fibroblast attachment to single rooted tooth surfaces following ultrasonic scaling and root planning: An in vitro study.

Context: One of the most important goals of periodontal therapy is connective tissue reattachment to previously diseased root surfaces. In the recent years, laser therapy has been considered as an important tool in improving the treatment of periodontal disease.

Aims: To evaluate the neodymium-doped yttrium aluminum garnet (Nd: YAG) lasers effects on root surfaces affected by periodontal disease and compare this treatment with scaling and root planning (SRP) in terms of fibroblast attachment.

RNase L interacts with Filamin A to regulate actin dynamics and barrier function for viral entry.

Unlabelled: The actin cytoskeleton and its network of associated proteins constitute a physical barrier that viruses must circumvent to gain entry into cells for productive infection. The mechanisms by which the physical signals of infection are sensed by the host to activate an innate immune response are not well understood. The antiviral endoribonuclease RNase L is ubiquitously expressed in a latent form and activated upon binding 2-5A, a unique oligoadenylate produced during viral infections.

RNase L contributes to experimentally induced type 1 diabetes onset in mice.

The cause of type 1 diabetes continues to be a focus of investigation. Studies have revealed that interferon α (IFNα) in pancreatic islets after viral infection or treatment with double-stranded RNA (dsRNA), a mimic of viral infection, is associated with the onset of type 1 diabetes. However, how IFNα contributes to the onset of type 1 diabetes is obscure.

Modulation of P-selection and platelet aggregation in chronic periodontitis: A clinical study.

Background: The primary etiologic factor of periodontitis is the subgingival infection with a group of Gram negative pathogens. Transient bacteremia in periodontitis patients underlie chronic production and systemic increases of various proinflammatory mediators, including Interleukin (IL)-1α, IL-6, C-reactive protein and Tumor necrosis factor (TNF)-α. P- selectin is a member of selectin family of cell surface receptor which is located in the membrane of the secretory granules (alpha granules) of platelets and in the membrane of the Weibel-Palade bodies of the vascular endothelial cells.

Epigallocatechin-3-gallate suppresses proinflammatory cytokines and chemokines induced by Toll-like receptor 9 agonists in prostate cancer cells.

Chronic inflammation of the prostate contributes to the increased risk of prostate cancer. Microbial pathogens in the prostate cause inflammation that leads to prostatitis and proliferative inflammatory atrophy frequently associated with the development of prostate cancer. Bacterial lipopolysaccharides and DNA mediate immune responses by engaging Toll-like receptor (TLR) 4 and 9, respectively.

RNase L induces autophagy via c-Jun N-terminal kinase and double-stranded RNA-dependent protein kinase signaling pathways.

Autophagy is a tightly regulated mechanism that mediates sequestration, degradation, and recycling of cellular proteins, organelles, and pathogens. Several proteins associated with autophagy regulate host responses to viral infections. Ribonuclease L (RNase L) is activated during viral infections and cleaves cellular and viral single-stranded RNAs, including rRNAs in ribosomes.

RNase L releases a small RNA from HCV RNA that refolds into a potent PAMP.

Triggering and propagating an intracellular innate immune response is essential for control of viral infections. RNase L is a host endoribonuclease and a pivotal component of innate immunity that cleaves viral and cellular RNA within single-stranded loops releasing small structured RNAs with 5'-hydroxyl (5'-OH) and 3'-monophosphoryl (3'-p) groups. In 2007, we reported that RNase L cleaves self RNA to produce small RNAs that function as pathogen-associated molecular patterns (PAMPs).

Small self-RNA generated by RNase L amplifies antiviral innate immunity.

Antiviral innate immunity is initiated in response to RNA molecules that are produced in virus-infected cells. These RNAs activate signalling cascades that activate the genes that encode alpha- and beta-interferon (IFN). Signalling occurs through the interaction of the RNAs with either of two pathogen recognition receptors, retinoic acid-inducible gene-I (RIG-I, also known as DDX58) and melanoma differentiation associated gene-5 (MDA5, also known as IFIH1), which contain amino-terminal caspase activation and recruitment domains (CARD) and carboxy-terminal DExD/H Box RNA helicase motifs.

An infectious retrovirus susceptible to an IFN antiviral pathway from human prostate tumors.

We recently reported identification of a previously undescribed gammaretrovirus genome, xenotropic murine leukemia virus-related virus (XMRV), in prostate cancer tissue from patients homozygous for a reduced activity variant of the antiviral enzyme RNase L. Here we constructed a full-length XMRV genome from prostate tissue RNA and showed that the molecular viral clone is replication-competent. XMRV replication in the prostate cancer cell line DU145 was sensitive to inhibition by IFN-beta.

Selection and cloning of poly(rC)-binding protein 2 and Raf kinase inhibitor protein RNA activators of 2',5'-oligoadenylate synthetase from prostate cancer cells.

The antiviral and antitumor functions of RNase L are enabled by binding to the allosteric effectors 5'-phosphorylated, 2',5'-linked oligoadenylates (2-5A). 2-5A is produced by interferon-inducible 2',5'-oligoadenylate synthetases (OAS) upon activation by viral double-stranded RNA (dsRNA). Because mutations in RNase L have been implicated as risk factors for prostate cancer, we sought to determine if OAS activators are present in prostate cancer cells.

Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant.

Ribonuclease L (RNase L) is an important effector of the innate antiviral response. Mutations or variants that impair function of RNase L, particularly R462Q, have been proposed as susceptibility factors for prostate cancer. Given the role of this gene in viral defense, we sought to explore the possibility that a viral infection might contribute to prostate cancer in individuals harboring the R462Q variant.