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Regulation of Antiviral Immunity by Mitochondrial Dynamics
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Mohsin Khan, Hasan Imam, Saiful Anam Mir
Severe acute respiratory syndrome-coronavirus (SARS-CoV) is a novel coronavirus recently emerged as a significantly fatal pathogen. How SARS-CoV cripples host cell’s antiviral response is not fully characterized yet. SARS-CoV encoded protein, ORF-9b (open reading frame-9b) localizes to OMM and downregulates Drp1 (Shi et al., 2014). It was also observed that this depletion in Drp1 level is independent of autophagy but dependent of proteasomal machinery. ORF-9b induces ubiquitination of Drp1 and its subsequent degradation by proteasome. In HEK293 cells, expression of ORF-9b caused ~ 70% reduction in Drp1 levels. Reduction in Drp1 level inhibits mitochondrial fragmentation and infected cells predominantly show elongated population of mitochondria. ORF-9b also targets the MAVS signalosome by seizing PCBP2 (poly C-binding protein 2) and the E3 ligase ITCH (Itchy E3 Ubiquitin Protein Ligase) to promote MAVS degradation. In summary, SARS-CoV ORF-9b interrupts with mitochondrial dynamics (Shi et al., 2014) to evade the host cell innate immunity.
Diagnosis: Nanosensors in Diagnosis and Medical Monitoring
Published in Harry F. Tibbals, Medical Nanotechnology and Nanomedicine, 2017
The same analytical and informatics capabilities that make it possible to realize the genome, proteome, and metabolome have also led to the concepts of the transcriptome, signalosome, and other constructs for the systematic study of the complexities of biology.
Helicobacter pylori infection
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Diane Bimczok, Anne Müller, Phillip D. Smith
Despite innate and adaptive immune responses to H. pylori, the bacteria persist in all infected persons who have not been treated with antibiotics, indicating that H. pylori has highly effective immune evasion mechanisms (see Table 26.1). After inoculation into the stomach, H. pylori utilize their helical shape, flagellar motility, and urease-mediated hydrolysis of urea to NH3 to penetrate the mucus layer and establish colonization. H. pylori can detoxify the reactive oxygen and nitrogen products of innate inflammatory cells through production of antioxidant enzymes, including superoxide dismutase, catalase, and arginase, as discussed earlier. H. pylori also has developed multiple mechanisms to evade phagocytosis by neutrophils and macrophages, also discussed earlier. Importantly, the tetra-acetylated lipid A with fatty acids of 16 and 18 carbons and the reduced phosphorylation of the LPS lipid A backbone contribute to rendering H. pylori LPS 1000-fold less biologically active than the LPS of other gram-negative bacteria. In addition, modification of the flagellin N-terminal TLR5 recognition site, with compensatory changes in the flagellin molecules that preserve motility, allows H. pylori to evade TLR5 binding. Also, the remarkable genomic plasticity of H. pylori, reflected in gene loss, gain, recombination, and mutation, has promoted bacterial strain divergence and altered outer membrane proteins such as BabA and BabB, which mediate attachment to Lewis B blood group antigens on gastric epithelial cells. In addition to evasion tactics and genomic plasticity, H. pylori activates anti-inflammatory responses through several mechanisms, including the activation of DCs, resulting in MyD88-dependent production of anti-inflammatory cytokines such as IL-10. H. pylori fucose, in contrast to mannose-expressing organisms, dissociates DC-SIGN signalosome proteins, thereby enhancing IL-10 expression in addition to decreasing secretion of pro-inflammatory cytokines IL-6 and IL-12. The induction of gastric Treg cells, which downregulate effector T-cell responses, is another prominent mechanism by which H. pylori modulates host inflammatory responses, as discussed earlier. Thus, H. pylori evades recognition, modifies attachment molecules, and downregulates the ensuing inflammatory response, thereby promoting persistent infection.
The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy
Published in mAbs, 2023
Christina Claus, Claudia Ferrara-Koller, Christian Klein
4–1BB is not constitutively expressed on T cells, but induced after T cell activation via TCR or CD3 (signal 1).1,20 For optimal co-stimulation (signal 2), 4–1BB has to be clustered on the cell surface, inducing the assembly of an intracellular signalosome.85 A simple trimerization of 4–1BB receptors is not sufficient because soluble 4–1BBL, being a homotrimer, cannot enable efficient 4–1BB downstream signaling.32,86 This leads to the conclusion that the assembly of a functional signalosome needs at least 4 or more 4–1BB receptors in close proximity clustered in a synapse (hyper-clustering). This can be provided naturally by membrane-bound trimeric 4–1BBL or artificially by a non-4-1BBL competing antibody crosslinking soluble 4–1BBL-trimerized 4–1BB receptors (as described for HOT-1030 or urelumab, Figure 1), or by a 4–1BB agonistic molecule that is crosslinked by another cell expressing FcγRIIB or a crosslinking target. It has been predicted that the size as well as the epitope of the 4–1BB agonist may play a role for optimal synapse formation. For example, for ND021/NM21-1480, targeting the N-terminal (membrane distal) 4–1BB-epitope lead to improved functionality compared to membrane-proximal epitopes.58 An optimal synapse space of 140 Å has also been predicted, potentially giving smaller molecules an advantage.72
Structure-function relationship of the platelet glycoprotein VI (GPVI) receptor: does it matter if it is a dimer or monomer?
Published in Platelets, 2021
Joanne C. Clark, Foteini-Nafsika Damaskinaki, Yam Fung Hilaire Cheung, Alexandre Slater, Steve P. Watson
Formation of the signalosome allows effector proteins including the tyrosine kinases Btk and Tec to come into contact with their substrate which is key for efficient downstream signal transduction and for the regulation and activation of phospholipase C γ2 (PLCγ2). In humans, inhibitors of Btk such as ibrutinib and acalabrutinib, or the absence of Btk (which gives rise to the immunodeficiency syndrome X-linked agammaglobulaemia), have been shown to inhibit the response to low concentrations of GPVI agonists and to delay the response to higher concentrations despite the marked loss of phosphorylation of PLCγ2[21]. While one explanation for this could be the presence of the related kinase, Tec, this is also inhibited over similar concentrations by most of the current ‘Btk’ inhibitors (albeit there are discrepant reports on this [21–23]). Furthermore, Btk has been shown to support PLCγ2 activation and GPVI signaling in transfected cell lines by acting as both an adaptor protein and a tyrosine kinase[21]. An inhibitor of Btk that has a greater selectivity over Tec and no other off-target effects is required to resolve these two explanations.
An update of cyclic nucleotide phosphodiesterase as a target for cardiac diseases
Published in Expert Opinion on Drug Discovery, 2021
Numerous studies have supported the notion that individual PDEs are tethered to a precise signalosome via binding partners in an isoform-specific manner, each containing unique cyclase, PDE, kinases, and/or other signaling molecules (Figure 1). The signalosomes control cyclic nucleotide signaling locally and specifically, which lead to different biological functions [27,28,34]. Promoting or disrupting isoform-specific protein-protein interactions within specific signalosome may yield a greater specificity compared to current PDE inhibitors. The disruption of protein-protein interaction is often achieved by small molecule compounds or peptides. For example, a peptide that induces the disruption of the Hsp20-PDE4D complex has been shown to promote PKA phosphorylation of Hsp20 and alleviate cardiac myocyte hypertrophy [28]. A small molecule or a peptide that disrupts the AKAP18-PKA complexes has been shown to increase cardiac myocyte contractility [28]. It remains to be examined whether targeting specialized signalosomes by disruption of protein-protein interaction might be efficacious in clinical settings.