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Redox Biology Jun 2019Mountainous evidence suggests that inflammation, cardiomyocyte apoptosis and pyroptosis are involved in the development of sepsis and sepsis-induced cardiomyopathy...
Mountainous evidence suggests that inflammation, cardiomyocyte apoptosis and pyroptosis are involved in the development of sepsis and sepsis-induced cardiomyopathy (SIC). Stimulator of interferon genes (STING) is an indispensable molecule that could regulate inflammation and immune response in multiple diseases. However, the role of STING in cardiovascular disease, especially SIC remains unclear. This study was designed to investigate the potential molecular mechanisms of STING in lipopolysaccharide (LPS)-induced cardiac injury using STING global knockout mice. In wild type mice and cardiomyocytes, LPS stimulation triggered the perinuclear translocation of STING, which further bound to Type-I interferons (IFN) regulatory factor 3 (IRF3) and phosphorylated IRF3. Phosphorylated (P-) IRF3 subsequently translocated into nucleus and increased the expression of NOD-like receptor protein 3 (NLRP3). Knockout of STING in mice significantly improved survival rate and cardiac function, apart from suppressing myocardial and serum inflammatory cytokines, apoptosis, as well as cardiomyocyte pyroptosis. In vitro experiments revealed that NLRP3 overexpression by adenovirus could offset protective effects of STING knockdown in LPS-induced cardiomyocytes. Additionally, LPS stimulation also promoted the production of intracellular reactive oxygen (ROS), which further induced the NLRP3 translocation to the cytoplasm from the nucleus. Dissociative TXNIP could directly interact with cytoplasmic NLRP3 and form inflammasome, eventually triggering cardiomyocyte injury. Collectively, our findings disclose that STING deficiency could alleviate LPS-induced SIC in mice. Hence, targeting STING in cardiomyocytes may be a promising therapeutic strategy for preventing SIC.
Topics: Animals; Apoptosis; Cytokines; Disease Models, Animal; Echocardiography; Heart Diseases; Interferon Regulatory Factor-3; Intracellular Space; Lipopolysaccharides; Male; Membrane Proteins; Mice; Myocytes, Cardiac; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Reactive Oxygen Species
PubMed: 31121492
DOI: 10.1016/j.redox.2019.101215 -
Applied Microbiology and Biotechnology May 2023Campylobacter jejuni, causing strong enteritis, is an unusual bacterium with numerous peculiarities. Chemotactically controlled motility in viscous milieu allows... (Review)
Review
Campylobacter jejuni, causing strong enteritis, is an unusual bacterium with numerous peculiarities. Chemotactically controlled motility in viscous milieu allows targeted navigation to intestinal mucus and colonization. By phase variation, quorum sensing, extensive O-and N-glycosylation and use of the flagellum as type-3-secretion system C. jejuni adapts effectively to environmental conditions. C. jejuni utilizes proteases to open cell-cell junctions and subsequently transmigrates paracellularly. Fibronectin at the basolateral side of polarized epithelial cells serves as binding site for adhesins CadF and FlpA, leading to intracellular signaling, which again triggers membrane ruffling and reduced host cell migration by focal adhesion. Cell contacts of C. jejuni results in its secretion of invasion antigens, which induce membrane ruffling by paxillin-independent pathway. In addition to fibronectin-binding proteins, other adhesins with other target structures and lectins and their corresponding sugar structures are involved in host-pathogen interaction. Invasion into the intestinal epithelial cell depends on host cell structures. Fibronectin, clathrin, and dynein influence cytoskeletal restructuring, endocytosis, and vesicular transport, through different mechanisms. C. jejuni can persist over a 72-h period in the cell. Campylobacter-containing vacuoles, avoid fusion with lysosomes and enter the perinuclear space via dynein, inducing signaling pathways. Secretion of cytolethal distending toxin directs the cell into programmed cell death, including the pyroptotic release of proinflammatory substances from the destroyed cell compartments. The immune system reacts with an inflammatory cascade by participation of numerous immune cells. The development of autoantibodies, directed not only against lipooligosaccharides, but also against endogenous gangliosides, triggers autoimmune diseases. Lesions of the epithelium result in loss of electrolytes, water, and blood, leading to diarrhea, which flushes out mucus containing C. jejuni. Together with the response of the immune system, this limits infection time. Based on the structural interactions between host cell and bacterium, the numerous virulence mechanisms, signaling, and effects that characterize the infection process of C. jejuni, a wide variety of targets for attenuation of the pathogen can be characterized. The review summarizes strategies of C. jejuni for host-pathogen interaction and should stimulate innovative research towards improved definition of targets for future drug development. KEY POINTS: • Bacterial adhesion of Campylobacter to host cells and invasion into host cells are strictly coordinated processes, which can serve as targets to prevent infection. • Reaction and signalling of host cell depend on the cell type. • Campylobacter virulence factors can be used as targets for development of antivirulence drug compounds.
Topics: Humans; Bacterial Proteins; Campylobacter jejuni; Fibronectins; Dyneins; Virulence Factors; Adhesins, Bacterial; Epithelial Cells; Bacterial Adhesion; Campylobacter Infections
PubMed: 36941439
DOI: 10.1007/s00253-023-12456-w -
Current Issues in Molecular Biology 2021During viral replication, herpesviruses utilize a unique strategy, termed nuclear egress, to translocate capsids from the nucleus into the cytoplasm. This initial... (Review)
Review
During viral replication, herpesviruses utilize a unique strategy, termed nuclear egress, to translocate capsids from the nucleus into the cytoplasm. This initial budding step transfers a newly formed capsid from within the nucleus, too large to fit through nuclear pores, through the inner nuclear membrane to the perinuclear space. The perinuclear enveloped virion must then fuse with the outer nuclear membrane to be released into the cytoplasm for further maturation, undergoing budding once again at the trans-Golgi network or early endosomes, and ultimately exit the cell non-lytically to spread infection. This first budding process is mediated by two conserved viral proteins, UL31 and UL34, that form a heterodimer called the nuclear egress complex (NEC). This review focuses on what we know about how the NEC mediates capsid transport to the perinuclear space, including steps prior to and after this budding event. Additionally, we discuss the involvement of other viral proteins in this process and how NEC-mediated budding may be regulated during infection.
Topics: Capsid; Cell Nucleus; Cytoplasm; Herpesviridae; Herpesviridae Infections; Humans; Nuclear Envelope; Viral Proteins; Virion
PubMed: 32764158
DOI: 10.21775/cimb.041.125 -
Physiological Research Nov 2018Resistance to vitamin D has been known for decades as vitamin D resistant rickets, caused by mutations of the gene encoding for vitamin D receptor (VDR). Findings of... (Review)
Review
Resistance to vitamin D has been known for decades as vitamin D resistant rickets, caused by mutations of the gene encoding for vitamin D receptor (VDR). Findings of extra-skeletal effects of vitamin D and learning of the molecular mechanisms used by its biologically active metabolite calcitriol revealed other ways leading to its impaired sensitivity. Calcitriol takes advantage of both genomic and non-genomic mechanisms through its binding to vitamin D receptor, located not only in the cell nuclei but also in a perinuclear space. On the genomic level the complex of calcitriol bound to VDR binds to the DNA responsive elements of the controlled gene in concert with another nuclear receptor, retinoid X receptor, and expression of the VDR itself is controlled by its own ligand. These elements were found not only in the promotor region, but are scattered over the gene DNA. The gene expression includes a number of nuclear transcription factors which interact with the responsive elements and with each other and learning how they operate would further contribute to revealing causes of the impaired vitamin D sensitivity. Finally, the examples of major disorders are provided, associated with impairment of the vitamin D function and its receptor.
Topics: Calcitriol; Humans; Mutation; Receptors, Calcitriol; Vitamin D; Vitamin D Deficiency
PubMed: 30484666
DOI: 10.33549/physiolres.934006 -
Journal of Virology May 2022Herpesviruses assemble new viral particles in the nucleus. These nucleocapsids bud through the inner nuclear membrane to produce enveloped viral particles in the...
Herpesviruses assemble new viral particles in the nucleus. These nucleocapsids bud through the inner nuclear membrane to produce enveloped viral particles in the perinuclear space before fusing with the outer nuclear membrane to reach the cytoplasm. This unusual route is necessary since viral capsids are too large to pass through nuclear pores. However, the transient perinuclear nucleocapsids (250 nm in diameter) are also larger than the width of the perinuclear space (30 to 50 nm). Interestingly, linker of the nucleoskeleton and cytoskeleton (LINC) components SUN and KASH connect the inner and outer nuclear membranes and regulate their spacing. Previous work by others on the related pseudorabies virus and human cytomegalovirus showed that they functionally interact with SUN proteins. To clarify the role of SUN proteins, we explored their impact on herpes simplex virus 1 (HSV-1), another herpesvirus. Using dominant negative SUN mutants and RNA interference, we show that HSV-1 propagation is dependent on the LINC complex. In contrast to pseudorabies virus, SUN2 disruption by either approach led to increased HSV-1 extracellular viral yields. This SUN2 dependency may be linked to its greater impact on perinuclear spacing in infected cells compared to SUN1. Finally, the virus itself seems to modulate perinuclear spacing. The large size of herpesviruses prevents them from travelling across the nuclear pores, and they instead egress across the two nuclear membranes, generating short-lived enveloped perinuclear virions. This poses a challenge as the perinuclear space is smaller than the virions. This implies the separation (unzipping) of the two nuclear membranes to accommodate the viral particles. The LINC complex bridges the two nuclear membranes and is an important regulator of perinuclear spacing. Work by others hint at its functional implication during pseudorabies virus and cytomegalovirus propagation. The present study probes the importance for HSV-1 of the SUN proteins, the LINC components found in the inner nuclear membrane. Using dominant negative constructs and RNA interference (RNAi), the data reveal that SUN2 exhibits antiviral propriety toward HSV-1, as disrupting the protein leads to increased viral yields. This is in contrast with that reported for pseudorabies and suggests that differences among herpesviruses may, once again, prevail.
Topics: Animals; Cell Nucleus; Herpesvirus 1, Human; Herpesvirus 1, Suid; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Nuclear Envelope; Nucleocapsid; Virion
PubMed: 35435724
DOI: 10.1128/jvi.00453-22 -
Frontiers in Cellular and Infection... 2023Ring finger protein 213 (RNF213) is a large E3 ubiquitin ligase with a molecular weight of 591 kDa that is associated with moyamoya disease, a rare cerebrovascular... (Review)
Review
Ring finger protein 213 (RNF213) is a large E3 ubiquitin ligase with a molecular weight of 591 kDa that is associated with moyamoya disease, a rare cerebrovascular disease. It is located in the cytosol and perinuclear space. Missense mutations in this gene have been found to be more prevalent in patients with moyamoya disease compared with that in healthy individuals. Understanding the molecular function of RNF213 could provide insights into moyamoya disease. RNF213 contains a C3HC4-type RING finger domain with an E3 ubiquitin ligase domain and six AAA+ adenosine triphosphatase (ATPase) domains. It is the only known protein with both AAA+ ATPase and ubiquitin ligase activities. Recent studies have highlighted the role of RNF213 in fighting against microbial infections, including viruses, parasites, bacteria, and chlamydiae. This review aims to summarize the recent research progress on the mechanisms of RNF213 in pathogenic infections, which will aid researchers in understanding the antimicrobial role of RNF213.
Topics: Humans; Moyamoya Disease; Ubiquitin-Protein Ligases; Genes, Regulator; Transcription Factors; Anti-Infective Agents; Adenosine Triphosphatases
PubMed: 37655297
DOI: 10.3389/fcimb.2023.1205355 -
Advances in Anatomy, Embryology, and... 2017Herpes simplex virus mediates multiple distinct fusion events during infection. HSV entry is initiated by fusion of the viral envelope with either the limiting membrane... (Review)
Review
Herpes simplex virus mediates multiple distinct fusion events during infection. HSV entry is initiated by fusion of the viral envelope with either the limiting membrane of a host cell endocytic compartment or the plasma membrane. In the infected cell during viral assembly, immature, enveloped HSV particles in the perinuclear space fuse with the outer nuclear membrane in a process termed de-envelopment. A cell infected with some strains of HSV with defined mutations spread to neighboring cells by a fusion event called syncytium formation. Two experimental methods, the transient cell-cell fusion approach and fusion from without, are useful surrogate assays of HSV fusion. These five fusion processes are considered in terms of their requirements, mechanism, and regulation. The execution and modulation of these events require distinct yet often overlapping sets of viral proteins and host cell factors. The core machinery of HSV gB, gD, and the heterodimer gH/gL is required for most if not all of the HSV fusion mechanisms.
Topics: Animals; Cell Fusion; Herpes Simplex; Humans; Simplexvirus; Viral Proteins; Virus Assembly; Virus Internalization
PubMed: 28528438
DOI: 10.1007/978-3-319-53168-7_2 -
Nature Communications Jun 2023The endoplasmic reticulum (ER) is an organelle of nucleated cells that produces proteins, lipids and oligosaccharides. ER volume and activity are increased upon...
The endoplasmic reticulum (ER) is an organelle of nucleated cells that produces proteins, lipids and oligosaccharides. ER volume and activity are increased upon induction of unfolded protein responses (UPR) and are reduced upon activation of ER-phagy programs. A specialized domain of the ER, the nuclear envelope (NE), protects the cell genome with two juxtaposed lipid bilayers, the inner and outer nuclear membranes (INM and ONM) separated by the perinuclear space (PNS). Here we report that expansion of the mammalian ER upon homeostatic perturbations results in TMX4 reductase-driven disassembly of the LINC complexes connecting INM and ONM and in ONM swelling. The physiologic distance between ONM and INM is restored, upon resolution of the ER stress, by asymmetric autophagy of the NE, which involves the LC3 lipidation machinery, the autophagy receptor SEC62 and the direct capture of ONM-derived vesicles by degradative LAMP1/RAB7-positive endolysosomes in a catabolic pathway mechanistically defined as micro-ONM-phagy.
Topics: Animals; Nuclear Envelope; Endoplasmic Reticulum Stress; Autophagy; Unfolded Protein Response; Endoplasmic Reticulum; Mammals
PubMed: 37311770
DOI: 10.1038/s41467-023-39172-3 -
The Journal of Clinical Investigation Jun 2020Although autophagy is generally protective, uncontrolled or excessive activation of autophagy can be detrimental. However, it is often difficult to distinguish death by...
Although autophagy is generally protective, uncontrolled or excessive activation of autophagy can be detrimental. However, it is often difficult to distinguish death by autophagy from death with autophagy, and whether autophagy contributes to death in cardiomyocytes (CMs) is still controversial. Excessive activation of autophagy induces a morphologically and biochemically defined form of cell death termed autosis. Whether autosis is involved in tissue injury induced under pathologically relevant conditions is poorly understood. In the present study, myocardial ischemia/reperfusion (I/R) induced autosis in CMs, as evidenced by cell death with numerous vacuoles and perinuclear spaces, and depleted intracellular membranes. Autosis was observed frequently after 6 hours of reperfusion, accompanied by upregulation of Rubicon, attenuation of autophagic flux, and marked accumulation of autophagosomes. Genetic downregulation of Rubicon inhibited autosis and reduced I/R injury, whereas stimulation of autosis during the late phase of I/R with Tat-Beclin 1 exacerbated injury. Suppression of autosis by ouabain, a cardiac glycoside, in humanized Na+,K+-ATPase-knockin mice reduced I/R injury. Taken together, these results demonstrate that autosis is significantly involved in I/R injury in the heart and triggered by dysregulated accumulation of autophagosomes due to upregulation of Rubicon.
Topics: Animals; Autophagosomes; Autophagy; Intracellular Signaling Peptides and Proteins; Mice; Mice, Transgenic; Myocardial Reperfusion Injury; Myocardium; Up-Regulation
PubMed: 32364533
DOI: 10.1172/JCI132366 -
Frontiers in Physiology 2018Since the discovery of the inner nuclear transmembrane protein emerin in the early 1990s, nuclear envelope (NE) components and related involvement in nuclei integrity... (Review)
Review
Since the discovery of the inner nuclear transmembrane protein emerin in the early 1990s, nuclear envelope (NE) components and related involvement in nuclei integrity and functionality have been highly investigated. The NE is composed of two distinct lipid bilayers described as the inner (INM) and outer (ONM) nuclear membrane. NE proteins can be specifically "integrated" in the INM (such as emerin and SUN proteins) or in the ONM such as nesprins. Additionally, flanked to the INM, the nuclear lamina, a proteinaceous meshwork mainly composed of lamins A and C completes NE composition. This network of proteins physically interplays to guarantee NE integrity and most importantly, shape the bridge between cytoplasmic cytoskeletons networks (such as microtubules and actin) and the genome, through the anchorage to the heterochromatin. The essential network driving the connection of nucleoskeleton with cytoskeleton takes place in the perinuclear space (the space between ONM and INM) with the contribution of the LINC complex (for Linker of Nucleoskeleton to Cytoskeleton), hosting KASH and SUN proteins interactions. This close interplay between compartments has been related to diverse functions from nuclear integrity, activity and positioning through mechanotransduction pathways. At the same time, mutations in NE components genes coding for proteins such as lamins or nesprins, had been associated with a wide range of congenital diseases including cardiac and muscular diseases. Although most of these NE associated proteins are ubiquitously expressed, a large number of tissue-specific disorders have been associated with diverse pathogenic mutations. Thus, diagnosis and molecular explanation of this group of diseases, commonly called "nuclear envelopathies," is currently challenging. This review aims, first, to give a better understanding of diverse functions of the LINC complex components, from the point of view of lamins and nesprins. Second, to summarize human congenital diseases with a special focus on muscle and heart abnormalities, caused by mutations in genes coding for these two types of NE associated proteins.
PubMed: 30245638
DOI: 10.3389/fphys.2018.01277