Viruses such as coxsackievirus B3 (CVB3) are entirely host cell-dependent parasites. Indeed, they must cleverly exploit various compartments of host cells to complete their life cycle, and ...consequently launch disease. Evolution has equipped this pico-rna-virus, CVB3, to use different strategies, including CVB3-induced direct damage to host cells followed by a host inflammatory response to CVB3 infection, and cell death to super-additively promote target organ tissue injury, and dysfunction. In this update, the patho-stratagems of CVB3 are explored from molecular, and systems-level approaches. In summarizing recent developments in this field, we focus particularly on mechanisms by which CVB3 can harness different host cell processes including kinases, host cell-killing and cell-eating machineries, matrix metalloproteinases and miRNAs to promote disease.
The ubiquitin-proteasome pathway in viral infections Gao, Guang; Luo, Honglin
Canadian journal of physiology and pharmacology,
2006, 2006-Jan, 20060101, Letnik:
84, Številka:
1
Conference Proceeding, Journal Article
Recenzirano
The cellular biological function of the ubiquitin-proteasome pathway as a major intracellular protein degradation pathway, and as an important modulator for the regulation of many fundamental ...cellular processes has been greatly appreciated over the last decade. The critical role of the ubiquitin-proteasome pathway in viral pathogenesis has become increasingly apparent. Many viruses have been reported to evolve different strategies to utilize the ubiquitin-proteasome pathway for their own benefits. Here, we review the general background and function of the ubiquitin-proteasome pathway, summarize our current understanding of how viruses use this pathway to target cellular proteins, and finally, discuss the roles of this pathway in enteroviral infection, and the potential therapeutic application of proteasome inhibition in myocarditis.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Long carbon fiber reinforced PA6 composites were injection-molded from pellets.•Novel core/shell structured pellets were produced by a scalable process.•Carbon fibers were treated with sizing agent ...to enhance interfacial bonding.•Concentration of sizing agent had an important impact on fiber–matrix adhesion.•The composites had improved performance in comparison to short fiber composites.
In this work, long carbon fiber reinforced polyamide 6 (LCF/PA6) composites were prepared by injection-molding a novel kind of core/shell pellets that were mass produced by a convenient and scalable process of melt impregnation assisted by a single screw extruder. The effect of fiber sizing treatment on fiber distribution, melt flowability, and mechanical properties of the LCF/PA6 composites was investigated. It was demonstrated that the melt flowability exhibited a continuous increase with the increase of sizing concentration while the mechanical properties showed peak values at a sizing concentration of 22wt.%. In addition, the mechanical properties of the LCF/PA6 composites at the optimal sizing concentration were examined as a function of the content of carbon fibers. These findings may provide guidance for the studies aimed at developing long carbon fiber reinforced thermoplastic composites with desirable mechanical properties.
Uniform dispersion of two-dimensional (2D) graphene materials in polymer matrices remains challenging. In this work, a novel layer-by-layer assembly strategy was developed to prepare a sophisticated ...nanostructure with highly dispersed 2D graphene oxide in a three-dimensional matrix consisting of one-dimensional bacterial cellulose (BC) nanofibers. This method is a breakthrough, with respect to the conventional static culture method for BC that involves multiple in situ layer-by-layer assembly steps at the interface between previously grown BC and the culture medium. In the as-prepared BC/GO nanocomposites, the GO nanosheets are mechanically bundled and chemically bonded with BC nanofibers via hydrogen bonding, forming an intriguing nanostructure. The sophisticated nanostructure of the BC/GO leads to greatly enhanced mechanical properties compared to those of bare BC. This strategy is versatile, facile, scalable, and can be promising for the development of high-performance BC-based nanocomposite hydrogels.
Micropatterned pores in scaffolds have been extensively used to promote mass transport, tissue integration, and vascularization. However, the combined effects of microchannels and biomimetic ...structure on cell functions have not been investigated. Herein, microchannels with varying diameters of about 100, 200, and 400 μm were fabricated in the scaffolds composed of nanofibrous (diameter < 100 nm) bacterial nanocellulose and submicro-fibrous (diameter = 100–1000 nm) saponified cellulose acetate. The nano-submicro-fibrous cellulose scaffolds with microchannels were fabricated by combining electrospinning, step-by-step in situ biosynthesis, and laser-aided punching. It is found that the presence of microchannels favors cell proliferation and migration at an optimum microchannel size. More importantly, the microchannels and nano-submicro-fibrous wall morphology show a synergistic effect in promoting cell migration. These results suggest that the biomimetic nano-submicro-fibrous cellulose scaffolds with microchannels show promising applications in tissue engineering and regenerative medicine.
Natural blood vessels possess a multi-layered structure. Herein, we present a bio-inspired double-layered integrated tubular graft with a compact inner layer and a porous outer layer. The inner layer ...consists of nanofibrous bacterial cellulose (BC) and microfibrous cellulose acetate (CA), which favors the adhesion and proliferation of endothelial cells (ECs). The outer layer, with hierarchical pores including nano-sized pores from pristine BC, median-sized pores (dozens of microns) created by particle leaching, and a large pore (hundreds of microns) array created by laser ablation, is appropriate for the penetration of vascular smooth muscle cells (SMCs). The in-situ biosynthesis was employed to "suture" the two layers, aiming to achieve an integrated tubular structure. The morphology, mechanical properties, and cell behavior of the tubular grafts were characterized. The in vitro study demonstrates that the unique outer layer possesses enhanced SMC penetration compared to the counterpart without hierarchical pores. Overall, the findings of this study demonstrate the potential of such a biomimetic integrated vascular graft for vascular replacement and regeneration.
The impact of graphene oxide (GO) on normal cells has been widely investigated. However, much less is known on its effect on cancer cells. Herein, GO nanosheets were incorporated into electrospun ...cellulose acetate (CA) microfibers. The GO-incorporated CA (GO/CA) microfibers were combined with bacterial cellulose (BC) nanofibers via in situ biosynthesis to obtain the nano-microfibrous scaffolds. The GO/CA–BC scaffolds were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS). The GO/CA–BC scaffolds were used for breast cancer cell culture to evaluate the effect of GO on cancer cell behavior. Fluorescence images revealed large multicellular clusters on the surface of GO/CA–BC scaffolds. Compared to the bare CA–BC scaffold, the GO/CA–BC scaffolds not only showed enhanced mechanical properties but also improved cell proliferation. It is expected that the GO/CA–BC scaffolds would provide a suitable microenvironment for the culture of cancer cells which is necessary for drug screening and cell biology study.
Graphic abstract
Genetic analyses of patients with amyotrophic lateral sclerosis (ALS) have revealed a strong association between mutations in genes encoding many RNA-binding proteins (RBPs), including TARDBP, FUS, ...hnRNPA1, hnRNPA2B1, MATR3, ATXN2, TAF15, TIA-1, and EWSR1, and disease onset/progression. RBPs are a group of evolutionally conserved proteins that participate in multiple steps of RNA metabolism, including splicing, polyadenylation, mRNA stability, localization, and translation. Dysregulation of RBPs, as a consequence of gene mutations, impaired nucleocytoplasmic trafficking, post-translational modification, aggregation and sequestration by abnormal RNA foci, has been shown to be involved in neurodegeneration and the development of ALS. While the exact mechanism by which dysregulated RBPs contribute to ALS remains elusive, emerging evidence supports the notion that both a loss-of-function and/or a gain-of-toxic-function of these ALS-linked RBPs play a significant role in disease pathogenesis through facilitating abnormal protein interaction, causing aberrant RNA metabolism, and by disturbing ribonucleoprotein granule dynamics and phase transition. In this review, we summarize the current knowledge on the molecular mechanism by which RBPs are dysregulated and the influence of defective RBPs on cellular homeostasis during the development of ALS. The strategies of ongoing clinical trials targeting RBPs and/or relevant processes are also discussed in the present review.
The adaptor protein, sequestosome 1 (SQSTM1)/p62, plays an essential role in mediating selective autophagy. It serves as an autophagy receptor targeting ubiquitinated proteins to autophagosomes for ...degradation. In addition, it functions as a scaffold protein to regulate signaling pathways. Here we explored the interplay between coxsackievirus B3 (CVB3) and SQSTM1-mediated selective autophagy. We reported that SQSTM1 was cleaved at glycine 241 following CVB3 infection through the activity of viral protease 2A
pro
. The resulting cleavage fragments of SQSTM1 were no longer the substrates of autophagy, and their ability to form protein aggregates was greatly decreased. Although the C-terminal truncation sustained the binding activity of SQSTM1 to microtubule-associated protein 1 light chain (LC3), it failed to interact with ubiquitinated proteins. It was also found that colocalization between the C-terminal fragment of SQSTM1 (SQSTM1-C) and LC3 and ubiquitin within the punctate structures was markedly disrupted. Moreover, we observed that SQSTM1-C retained the ability of SQSTM1 to stabilize antioxidant transcription factor NFE2L2 nuclear factor (erythroid-derived 2)-like 2; however, both the N-terminal fragment of SQSTM1 (SQSTM1-N) and SQSTM1-C lost the function of SQSTM1 in activating NFKB (the nuclear factor of kappa light polypeptide gene enhancer in B-cells) pathway. Collectively, our results suggest a novel model by which cleavage of SQSTM1 as a result of CVB3 infection impairs the function of SQSTM1 in selective autophagy and host defense signaling.
Coxsackievirus B3 (CVB3) is a single-stranded positive RNA virus that usurps cellular machinery, including the evolutionarily anti-viral autophagy pathway, for productive infections. Despite the ...emergence of double-membraned autophagosome-like vesicles during CVB3 infection, very little is known about the mechanism of autophagy initiation. In this study, we investigated the role of established autophagy factors in the initiation of CVB3-induced autophagy. Using siRNA-mediated gene-silencing and CRISPR-Cas9-based gene-editing in culture cells, we discovered that CVB3 bypasses the ULK1/2 and PI3K complexes to trigger autophagy. Moreover, we found that CVB3-induced LC3 lipidation occurred independent of WIPI2 and the transmembrane protein ATG9 but required components of the late-stage ubiquitin-like ATG conjugation system including ATG5 and ATG16L1. Remarkably, we showed the canonical autophagy factor ULK1 was cleaved through the catalytic activity of the viral proteinase 3C. Mutagenesis experiments identified the cleavage site of ULK1 after Q524, which separates its N-terminal kinase domain from C-terminal substrate binding domain. Finally, we uncovered PI4KIIIβ (a PI4P kinase), but not PI3P or PI5P kinases as requisites for CVB3-induced LC3 lipidation. Taken together, our studies reveal that CVB3 initiates a non-canonical form of autophagy that bypasses ULK1/2 and PI3K signaling pathways to ultimately converge on PI4KIIIβ- and ATG5-ATG12-ATG16L1 machinery.
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