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PLoS Pathogens Aug 2022A dysregulated proinflammatory cytokine response is characteristic of severe coronavirus infections caused by SARS-CoV-2, yet our understanding of the underlying...
A dysregulated proinflammatory cytokine response is characteristic of severe coronavirus infections caused by SARS-CoV-2, yet our understanding of the underlying mechanism responsible for this imbalanced immune response remains incomplete. Processing bodies (PBs) are cytoplasmic membraneless ribonucleoprotein granules that control innate immune responses by mediating the constitutive decay or suppression of mRNA transcripts, including many that encode proinflammatory cytokines. PB formation promotes turnover or suppression of cytokine RNAs, whereas PB disassembly corresponds with the increased stability and/or translation of these cytokine RNAs. Many viruses cause PB disassembly, an event that can be viewed as a switch that rapidly relieves cytokine RNA repression and permits the infected cell to respond to viral infection. Prior to this submission, no information was known about how human coronaviruses (CoVs) impacted PBs. Here, we show SARS-CoV-2 and the common cold CoVs, OC43 and 229E, induced PB loss. We screened a SARS-CoV-2 gene library and identified that expression of the viral nucleocapsid (N) protein from SARS-CoV-2 was sufficient to mediate PB disassembly. RNA fluorescent in situ hybridization revealed that transcripts encoding TNF and IL-6 localized to PBs in control cells. PB loss correlated with the increased cytoplasmic localization of these transcripts in SARS-CoV-2 N protein-expressing cells. Ectopic expression of the N proteins from five other human coronaviruses (OC43, MERS, 229E, NL63 and SARS-CoV) did not cause significant PB disassembly, suggesting that this feature is unique to SARS-CoV-2 N protein. These data suggest that SARS-CoV-2-mediated PB disassembly contributes to the dysregulation of proinflammatory cytokine production observed during severe SARS-CoV-2 infection.
Topics: COVID-19; Coronavirus OC43, Human; Cytokines; Humans; In Situ Hybridization, Fluorescence; Processing Bodies; RNA; SARS-CoV-2
PubMed: 35998203
DOI: 10.1371/journal.ppat.1010724 -
PloS One 2023Messenger RNA processing bodies (P-bodies) are cytoplasmic membrane-free organelles that contain proteins involved in mRNA silencing, storage and decay. The mechanism by...
Messenger RNA processing bodies (P-bodies) are cytoplasmic membrane-free organelles that contain proteins involved in mRNA silencing, storage and decay. The mechanism by which P-body components interact and the factors that regulate the stability of these structures are incompletely understood. In this study, we used a fluorescence-based, two-hybrid assay to investigate interactions between P-body components that occur inside the cell. LSm14a, PATL1, XRN1, and NBDY were found to interact with the N-terminal, WD40-domain-containing portion of EDC4. The N-terminus of full-length PATL1 was required to mediate the interaction between EDC4 and DDX6. The C-terminal, alpha helix-domain- containing portion of EDC4 was sufficient to mediate interaction with DCP1a and CCHCR1. In the absence of endogenous P-bodies, caused by depletion of LSm14a or DDX6, expression of the portion of EDC4 that lacked the N-terminus retained the ability to form cytoplasmic dots that were indistinguishable from P-bodies at the level of UV light microscopy. Despite the absence of endogenous P-bodies, this portion of EDC4 was able to recruit DCP1a, CCHCR1 and EDC3 to cytoplasmic dots. The results of this study permit the development of a new model of P-body formation and suggest that the N-terminus of EDC4 regulates the stability of these structures.
Topics: Animals; Processing Bodies; Cell Membrane; Cytoplasm; Cytosol; Mammals; RNA, Messenger
PubMed: 36877681
DOI: 10.1371/journal.pone.0282496 -
Journal of Molecular Biology Aug 2023The cellular defense against viruses involves the assembly of oligomers, granules and membraneless organelles (MLOs) that govern the activation of several arms of the... (Review)
Review
The cellular defense against viruses involves the assembly of oligomers, granules and membraneless organelles (MLOs) that govern the activation of several arms of the innate immune response. Upon interaction with specific pathogen-derived ligands, a number of pattern recognition receptors (PRRs) undergo phase-separation thus triggering downstream signaling pathways. Among other relevant condensates, inflammasomes, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) specks, cyclic GMP-AMP synthase (cGAS) foci, protein kinase R (PKR) clusters, ribonuclease L-induced bodies (RLBs), stress granules (SGs), processing bodies (PBs) and promyelocytic leukemia protein nuclear bodies (PML NBs) play different roles in the immune response. In turn, viruses have evolved diverse strategies to evade the host defense. Viral DNA or RNA, as well as viral proteases or proteins carrying intrinsically disordered regions may interfere with condensate formation and function in multiple ways. In this review we discuss current and hypothetical mechanisms of viral escape that involve the disassembly, repurposing, or inactivation of membraneless condensates that govern innate immunity. We summarize emerging interconnections between these diverse condensates that ultimately determine the cellular outcome.
Topics: Biomolecular Condensates; Immunity, Innate; Signal Transduction; Viruses; Immune Evasion
PubMed: 36702393
DOI: 10.1016/j.jmb.2023.167976 -
PLoS Biology Jul 2023Microglia-mediated neuroinflammation is involved in various neurological diseases, including ischemic stroke, but the endogenous mechanisms preventing unstrained...
Microglia-mediated neuroinflammation is involved in various neurological diseases, including ischemic stroke, but the endogenous mechanisms preventing unstrained inflammation is still unclear. The anti-inflammatory role of transcription factor nuclear receptor subfamily 4 group A member 1 (NR4A1) in macrophages and microglia has previously been identified. However, the endogenous mechanisms that how NR4A1 restricts unstrained inflammation remain elusive. Here, we observed that NR4A1 is up-regulated in the cytoplasm of activated microglia and localizes to processing bodies (P-bodies). In addition, we found that cytoplasmic NR4A1 functions as an RNA-binding protein (RBP) that directly binds and destabilizes Tnf mRNA in an N6-methyladenosine (m6A)-dependent manner. Remarkably, conditional microglial deletion of Nr4a1 elevates Tnf expression and worsens outcomes in a mouse model of ischemic stroke, in which case NR4A1 expression is significantly induced in the cytoplasm of microglia. Thus, our study illustrates a novel mechanism that NR4A1 posttranscriptionally regulates Tnf expression in microglia and determines stroke outcomes.
Topics: Animals; Mice; Transcription Factors; Microglia; Stroke; Ischemic Stroke; Inflammation; RNA, Messenger
PubMed: 37486903
DOI: 10.1371/journal.pbio.3002199 -
Wiley Interdisciplinary Reviews.... 2015During communication, we perceive and express emotional information through many different channels, including facial expressions, prosody, body motion, and posture.... (Review)
Review
During communication, we perceive and express emotional information through many different channels, including facial expressions, prosody, body motion, and posture. Although historically the human body has been perceived primarily as a tool for actions, there is now increased understanding that the body is also an important medium for emotional expression. Indeed, research on emotional body language is rapidly emerging as a new field in cognitive and affective neuroscience. This article reviews how whole-body signals are processed and understood, at the behavioral and neural levels, with specific reference to their role in emotional communication. The first part of this review outlines brain regions and spectrotemporal dynamics underlying perception of isolated neutral and affective bodies, the second part details the contextual effects on body emotion recognition, and final part discusses body processing on a subconscious level. More specifically, research has shown that body expressions as compared with neutral bodies draw upon a larger network of regions responsible for action observation and preparation, emotion processing, body processing, and integrative processes. Results from neurotypical populations and masking paradigms suggest that subconscious processing of affective bodies relies on a specific subset of these regions. Moreover, recent evidence has shown that emotional information from the face, voice, and body all interact, with body motion and posture often highlighting and intensifying the emotion expressed in the face and voice.
Topics: Brain Mapping; Cognitive Science; Emotions; Facial Expression; Humans; Kinesics; Visual Perception; Voice
PubMed: 26263069
DOI: 10.1002/wcs.1335 -
Plants (Basel, Switzerland) Aug 2020RNA granules, such as stress granules and processing bodies, can balance the storage, degradation, and translation of mRNAs in diverse eukaryotic organisms. The sessile... (Review)
Review
RNA granules, such as stress granules and processing bodies, can balance the storage, degradation, and translation of mRNAs in diverse eukaryotic organisms. The sessile nature of plants demands highly versatile strategies to respond to environmental fluctuations. In this review, we discuss recent findings of the dynamics and functions of these RNA granules in plants undergoing developmental reprogramming or responding to environmental stresses. Special foci include the dynamic assembly, disassembly, and regulatory roles of these RNA granules in determining the fate of mRNAs.
PubMed: 32872650
DOI: 10.3390/plants9091122 -
Journal of Neurogenetics Jun 2016Taste allows animals to discriminate the value and potential toxicity of food prior to ingestion. Many tastants elicit an innate attractive or avoidance response that is... (Review)
Review
Taste allows animals to discriminate the value and potential toxicity of food prior to ingestion. Many tastants elicit an innate attractive or avoidance response that is modifiable with nutritional state and prior experience. A powerful genetic tool kit, well-characterized gustatory system, and standardized behavioral assays make the fruit fly, Drosophila melanogaster, an excellent system for investigating taste processing and memory. Recent studies have used this system to identify the neural basis for acquired taste preference. These studies have revealed a role for dopamine-mediated plasticity of the mushroom bodies that modulate the threshold of response to appetitive tastants. The identification of neural circuitry regulating taste memory provides a system to study the genetic and physiological processes that govern plasticity within a defined memory circuit.
Topics: Animals; Drosophila melanogaster; Memory; Mushroom Bodies; Taste; Taste Perception
PubMed: 27328844
DOI: 10.1080/01677063.2016.1185104 -
Annual Review of Vision Science Sep 2022Visual representations of bodies, in addition to those of faces, contribute to the recognition of con- and heterospecifics, to action recognition, and to nonverbal... (Review)
Review
Visual representations of bodies, in addition to those of faces, contribute to the recognition of con- and heterospecifics, to action recognition, and to nonverbal communication. Despite its importance, the neural basis of the visual analysis of bodies has been less studied than that of faces. In this article, I review what is known about the neural processing of bodies, focusing on the macaque temporal visual cortex. Early single-unit recording work suggested that the temporal visual cortex contains representations of body parts and bodies, with the dorsal bank of the superior temporal sulcus representing bodily actions. Subsequent functional magnetic resonance imaging studies in both humans and monkeys showed several temporal cortical regions that are strongly activated by bodies. Single-unit recordings in the macaque body patches suggest that these represent mainly body shape features. More anterior patches show a greater viewpoint-tolerant selectivity for body features, which may reflect a processing principle shared with other object categories, including faces.
Topics: Animals; Brain Mapping; Humans; Macaca; Pattern Recognition, Visual; Photic Stimulation; Temporal Lobe
PubMed: 35610000
DOI: 10.1146/annurev-vision-100720-113429 -
Wiley Interdisciplinary Reviews. RNA Nov 2020In bacteria, mRNA decay is controlled by megadalton scale macromolecular assemblies called, "RNA degradosomes," composed of nucleases and other RNA decay associated... (Review)
Review
In bacteria, mRNA decay is controlled by megadalton scale macromolecular assemblies called, "RNA degradosomes," composed of nucleases and other RNA decay associated proteins. Recent advances in bacterial cell biology have shown that RNA degradosomes can assemble into phase-separated structures, termed bacterial ribonucleoprotein bodies (BR-bodies), with many analogous properties to eukaryotic processing bodies and stress granules. This review will highlight the functional role that BR-bodies play in the mRNA decay process through its organization into a membraneless organelle in the bacterial cytoplasm. This review will also highlight the phylogenetic distribution of BR-bodies across bacterial species, which suggests that these phase-separated structures are broadly distributed across bacteria, and in evolutionarily related mitochondria and chloroplasts. This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Export and Localization > RNA Localization RNA Turnover and Surveillance > Regulation of RNA Stability.
Topics: Bacteria; Chloroplasts; Mitochondria; RNA, Messenger; Ribonucleoproteins
PubMed: 32445438
DOI: 10.1002/wrna.1599 -
Methods in Molecular Biology (Clifton,... 2023Multiple E. coli cultivations, producing recombinant proteins, lead to the formation of inclusion bodies (IBs). IBs historically were considered as nondesired...
Multiple E. coli cultivations, producing recombinant proteins, lead to the formation of inclusion bodies (IBs). IBs historically were considered as nondesired by-products, due to their time- and cost-intensive purification. Nowadays, many obstacles in IB processing can be overcome. As a consequence, several industrial processes with E. coli favor IB formation over soluble production options due to the high space time yields obtained. Within this chapter, we discuss the state-of-the art biopharmaceutical IB process, review its challenges, highlight the recent developments and perspectives, and also propose alternative solutions, compared to the state-of-the art processing.
Topics: Escherichia coli; Inclusion Bodies; Recombinant Proteins
PubMed: 36656513
DOI: 10.1007/978-1-0716-2930-7_1