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Journal articleEndres R, Cavanagh H, Mosbach A, et al., 6424,
Physics-informed deep learning characterizes morphodynamics of Asian soybean rust disease
, Nature Communications, Vol: 12, Pages: 1-8, ISSN: 2041-1723Medicines and agricultural biocides are often discovered using large phenotypic screens across hundreds of compounds, where visible effects of whole organisms are compared to gauge efficacy and possible modes of action. However, such analysis is often limited to human-defined and static features. Here, we introduce a novel framework that can characterize shape changes (morphodynamics) for cell-drug interactions directly from images, and use it to interpret perturbed development of Phakopsora pachyrhizi, the Asian soybean rust crop pathogen. We describe population development over a 2D space of shapes (morphospace) using two models with condition-dependent parameters: a top-down Fokker-Planck model of diffusive development over Waddington-type landscapes, and a bottom-up model of tip growth. We discover a variety of landscapes, describing phenotype transitions during growth, and identify possible perturbations in the tip growth machinery that cause this variation. This demonstrates a widely-applicable integration of unsupervised learning and biophysical modeling.
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Journal articleMiliara X, Tatsuta T, Eiyama A, et al., 2023,
An intermolecular hydrogen bonded network in the PRELID-TRIAP protein family plays a role in lipid sensing.
, Biochim Biophys Acta Proteins Proteom, Vol: 1871The PRELID-TRIAP1 family of proteins is responsible for lipid transfer in mitochondria. Multiple structures have been resolved of apo and lipid substrate bound forms, allowing us to begin to piece together the molecular level details of the full lipid transfer cycle. Here, we used molecular dynamics simulations to demonstrate that the lipid binding is mediated by an extended, water-mediated hydrogen bonding network. A key mutation, R53E, was found to disrupt this network, causing lipid to be released from the complex. The X-ray crystal structure of R53E was captured in a fully closed and apo state. Lipid transfer assays and molecular simulations allow us to interpret the observed conformation in the context of the biological role. Together, our work provides further understanding of the mechanistic control of lipid transport by PRELID-TRIAP1 in mitochondria.
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Journal articleBaxter JM, Hutchison CDM, Maghlaoui K, et al., 2022,
Observation of Cation Chromophore Photoisomerization of a Fluorescent Protein Using Millisecond Synchrotron Serial Crystallography and Infrared Vibrational and Visible Spectroscopy.
, J Phys Chem B, Vol: 126, Pages: 9288-9296The chromophores of reversibly switchable fluorescent proteins (rsFPs) undergo photoisomerization of both the trans and cis forms. Concurrent with cis/trans photoisomerisation, rsFPs typically become protonated on the phenolic oxygen resulting in a blue shift of the absorption. A synthetic rsFP referred to as rsEospa, derived from EosFP family, displays the same spectroscopic behavior as the GFP-like rsFP Dronpa at pH 8.4 and involves the photoconversion between nonfluorescent neutral and fluorescent anionic chromophore states. Millisecond time-resolved synchrotron serial crystallography of rsEospa at pH 8.4 shows that photoisomerization is accompanied by rearrangements of the same three residues as seen in Dronpa. However, at pH 5.5 we observe that the OFF state is identified as the cationic chromophore with additional protonation of the imidazolinone nitrogen which is concurrent with a newly formed hydrogen bond with the Glu212 carboxylate side chain. FTIR spectroscopy resolves the characteristic up-shifted carbonyl stretching frequency at 1713 cm-1 for the cationic species. Electronic spectroscopy furthermore distinguishes the cationic absorption band at 397 nm from the neutral species at pH 8.4 seen at 387 nm. The observation of photoisomerization of the cationic chromophore state demonstrates the conical intersection for the electronic configuration, where previously fluorescence was proposed to be the main decay route for states containing imidazolinone nitrogen protonation. We present the full time-resolved room-temperature X-ray crystallographic, FTIR, and UV/vis assignment and photoconversion modeling of rsEospa.
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Journal articleCamara M, Filloux A, 2022,
Supporting the strategic pillars of translational research in biofilms.
, NPJ Biofilms Microbiomes, Vol: 8 -
Journal articleJaureguiberry P, Titeux N, Wiemers M, et al., 2022,
The direct drivers of recent global anthropogenic biodiversity loss.
, Sci Adv, Vol: 8Effective policies to halt biodiversity loss require knowing which anthropogenic drivers are the most important direct causes. Whereas previous knowledge has been limited in scope and rigor, here we statistically synthesize empirical comparisons of recent driver impacts found through a wide-ranging review. We show that land/sea use change has been the dominant direct driver of recent biodiversity loss worldwide. Direct exploitation of natural resources ranks second and pollution third; climate change and invasive alien species have been significantly less important than the top two drivers. The oceans, where direct exploitation and climate change dominate, have a different driver hierarchy from land and fresh water. It also varies among types of biodiversity indicators. For example, climate change is a more important driver of community composition change than of changes in species populations. Stopping global biodiversity loss requires policies and actions to tackle all the major drivers and their interactions, not some of them in isolation.
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Journal articleRasmussen HØ, Kumar A, Shin B, et al., 2022,
FapA is an intrinsically disordered chaperone for Pseudomonas functional amyloid FapC.
, J Mol BiolBacterial functional amyloids contribute to biofilm development by bacteria and provide protection from the immune system and prevent antibiotic treatment. Strategies to target amyloid formation and interrupt biofilm formation have attracted recent interest due to their antimicrobial potential. Functional amyloid in Pseudomonas (Fap) includes FapC as the major component of the fibril while FapB is a minor component suggested to function as a nucleator of FapC. The system also includes the small periplasmic protein FapA, which has been shown to regulate fibril composition and morphology. The interplay between these three components is central in Fap fibril biogenesis. Here we present a comprehensive biophysical and spectroscopy analysis of FapA, FapB and FapC and provide insight into their molecular interactions. We show that all three proteins are primarily disordered with some regions with structural propensities for α-helix and β-sheet. FapA inhibits FapC fibrillation by targeting the nucleation step, whereas for FapB the elongation step is modulated. Furthermore, FapA alters the morphology of FapC (more than FapB) fibrils. Complex formation is observed between FapA and FapC, but not between FapA and FapB, and likely involves the N-terminus of FapA. We conclude that FapA is an intrinsically disordered chaperone for FapC that guards against fibrillation within the periplasm. This new understanding of a natural protective mechanism of Pseudomonas against amyloid formations can serve as inspiration for strategies blocking biofilm formation in infections.
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Journal articleFu Z, Ciais P, Feldman AF, et al., 2022,
Critical soil moisture thresholds of plant water stress in terrestrial ecosystems.
, Sci Adv, Vol: 8Plant water stress occurs at the point when soil moisture (SM) limits transpiration, defining a critical SM threshold (θcrit). Knowledge of the spatial distribution of θcrit is crucial for future projections of climate and water resources. Here, we use global eddy covariance observations to quantify θcrit and evaporative fraction (EF) regimes. Three canonical variables describe how EF is controlled by SM: the maximum EF (EFmax), θcrit, and slope (S) between EF and SM. We find systematic differences of these three variables across biomes. Variation in θcrit, S, and EFmax is mostly explained by soil texture, vapor pressure deficit, and precipitation, respectively, as well as vegetation structure. Dryland ecosystems tend to operate at low θcrit and show adaptation to water deficits. The negative relationship between θcrit and S indicates that dryland ecosystems minimize θcrit through mechanisms of sustained SM extraction and transport by xylem. Our results further suggest an optimal adaptation of local EF-SM response that maximizes growing-season evapotranspiration and photosynthesis.
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Journal articleChukhutsina VU, Baxter JM, Fadini A, et al., 2022,
Light activation of Orange Carotenoid Protein reveals bicycle-pedal single-bond isomerization.
, Nat Commun, Vol: 13Orange Carotenoid protein (OCP) is the only known photoreceptor which uses carotenoid for its activation. It is found exclusively in cyanobacteria, where it functions to control light-harvesting of the photosynthetic machinery. However, the photochemical reactions and structural dynamics of this unique photosensing process are not yet resolved. We present time-resolved crystal structures at second-to-minute delays under bright illumination, capturing the early photoproduct and structures of the subsequent reaction intermediates. The first stable photoproduct shows concerted isomerization of C9'-C8' and C7'-C6' single bonds in the bicycle-pedal (s-BP) manner and structural changes in the N-terminal domain with minute timescale kinetics. These are followed by a thermally-driven recovery of the s-BP isomer to the dark state carotenoid configuration. Structural changes propagate to the C-terminal domain, resulting, at later time, in the H-bond rupture of the carotenoid keto group with protein residues. Solution FTIR and UV/Vis spectroscopy support the single bond isomerization of the carotenoid in the s-BP manner and subsequent thermal structural reactions as the basis of OCP photoreception.
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Journal articleJoshi J, Stocker BD, Hofhansl F, et al., 2022,
Towards a unified theory of plant photosynthesis and hydraulics
, NATURE PLANTS, ISSN: 2055-026X -
Journal articleCioce A, Calle B, Rizou T, et al., 2022,
Cell-specific bioorthogonal tagging of glycoproteins
, NATURE COMMUNICATIONS, Vol: 13 -
Journal articleWesterband AC, Wright IJ, Maire V, et al., 2022,
Coordination of photosynthetic traits across soil and climate gradients.
, Glob Chang Biol"Least-cost theory" posits that C3 plants should balance rates of photosynthetic water loss and carboxylation in relation to the relative acquisition and maintenance costs of resources required for these activities. Here we investigated the dependency of photosynthetic traits on climate and soil properties using a new Australia-wide trait dataset spanning 528 species from 67 sites. We tested the hypotheses that plants on relatively cold or dry sites, or on relatively more fertile sites, would typically operate at greater CO2 drawdown (lower ratio of leaf internal to ambient CO2 , Ci :Ca ) during light-saturated photosynthesis, and at higher leaf N per area (Narea ) and higher carboxylation capacity (Vcmax 25 ) for a given rate of stomatal conductance to water, gsw . These results would be indicative of plants having relatively higher water costs than nutrient costs. In general, our hypotheses were supported. Soil total phosphorus (P) concentration and (more weakly) soil pH exerted positive effects on the Narea -gsw and Vcmax 25 -gsw slopes, and negative effects on Ci :Ca . The P effect strengthened when the effect of climate was removed via partial regression. We observed similar trends with increasing soil cation exchange capacity and clay content, which affect soil nutrient availability, and found that soil properties explained similar amounts of variation in the focal traits as climate did. Although climate typically explained more trait variation than soil did, together they explained up to 52% of variation in the slope relationships and soil properties explained up to 30% of the variation in individual traits. Soils influenced photosynthetic traits as well as their coordination. In particular, the influence of soil P likely reflects the Australia's geologically ancient low-relief landscapes with highly leached soils. Least-cost theory provides a valuable framework for understanding trade-offs between resource costs and use in plants, including limitin
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Journal articleBenns HJ, Storch M, Falco JA, et al., 2022,
CRISPR-based oligo recombineering prioritizes apicomplexan cysteines for drug discovery
, NATURE MICROBIOLOGY, Vol: 7, Pages: 1891-+, ISSN: 2058-5276 -
Journal articleGonzalo X, Yrah S, Broda A, et al., 2022,
Performance of lipid fingerprint by routine matrix-assisted laser desorption/ionization time of flight for the diagnosis of Mycobacterium tuberculosis complex species.
, Clin Microbiol InfectOBJECTIVES: Rapid detection of bacterial pathogens at species and sub-species levels is crucial for appropriate treatment, infection control, and public health management. Currently, one of the challenges in clinical microbiology is the discrimination of mycobacterial sub-species within the M. tuberculosis complex (MTBC). Our objective was to evaluate the ability of a biosafe mycobacterial lipid-based approach to identify MTBC cultures and sub-species. METHODS: A blinded study was conducted using 90 mycobacterial clinical isolate strains comprising MTBC strains sub-cultured in Middlebrook 7H11 medium supplemented with 10% oleic-acid, dextrose, catalase growth supplement and incubated for up to 6 weeks at 37°C and using the following seven reference strains (M. tuberculosis H37Rv, M canettii, M. africanum, M. pinnipedii, M. caprae, M. bovis, and M. bovis BCG) grown under the same conditions, to set the reference lipid database and test it against the 90 MTBC clinical isolates. Cultured mycobacteria were heat-inactivated and loaded onto the matrix-assisted laser desorption/ionization target followed by the addition of the matrix. Acquisition of the data was performed using the positive ion mode. RESULTS: Based on the identification of clear and defined lipid signatures from the seven reference strains, the method that we developed was fast (<10 minutes) and produced interpretable profiles for all but four isolates, caused by poor ionization giving an n = 86 with interpretable spectra. The sensitivity and specificity of the matrix-assisted laser desorption/ionization time of flight were 94.4 (95% CI, 86.4-98.5) and 94.4 (95% CI, 72.7-99.9), respectively. CONCLUSIONS: Mycobacterial lipid profiling provides a means of rapid, safe, and accurate discrimination of species within the MTBC.
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Journal articleZhu Z, Wang H, Harrison SP, et al., 2022,
Optimality principles explaining divergent responses of alpine vegetation to environmental change
, GLOBAL CHANGE BIOLOGY, ISSN: 1354-1013 -
Journal articleAntoniadi I, Mateo-Bonmati E, Pernisova M, et al., 2022,
IPT9, a cis-zeatin cytokinin biosynthesis gene, promotes root growth
, FRONTIERS IN PLANT SCIENCE, Vol: 13, ISSN: 1664-462X -
Journal articleWu G, Grassi P, MacIntyre DA, et al., 2022,
N-glycosylation of cervicovaginal fluid reflects microbial community, immune activity, and pregnancy status
, SCIENTIFIC REPORTS, Vol: 12, ISSN: 2045-2322 -
Journal articleStemkovski M, Bell JR, Ellwood ER, et al., 2022,
Disorder or a new order: How climate change affects phenological variability
, ECOLOGY, ISSN: 0012-9658 -
Journal articleDel Vecchio C, Daniels BC, Brancaccio G, et al., 2022,
Impact of antigen test target failure and testing strategies on the transmission of SARS-CoV-2 variants
, NATURE COMMUNICATIONS, Vol: 13 -
Journal articleMathavan I, Liu LJ, Robinson SW, et al., 2022,
Identification of Inhibitors of the Schistosoma mansoni VKR2 Kinase Domain
, ACS MEDICINAL CHEMISTRY LETTERS, ISSN: 1948-5875 -
Journal articleRansome E, Hobbs F, Jones S, et al., 2022,
Evaluating the transmission risk of SARS-CoV-2 from sewage pollution.
, Sci Total Environ, Vol: 858The presence of SARS-CoV-2 in untreated sewage has been confirmed in many countries but its incidence and infection risk in contaminated waters is poorly understood. The River Thames in the UK receives untreated sewage from 57 Combined Sewer Overflows (CSOs), with many discharging dozens of times per year. This study investigated if such discharges provide a pathway for environmental transmission of SARS-CoV-2. Samples of wastewater, surface water, and sediment collected close to six CSOs on the River Thames were assayed over eight months for SARS-CoV-2 RNA and infectious virus. Bivalves were also sampled as an indicator species of viral bioaccumulation. Sediment and water samples from the Danube and Sava rivers in Serbia, where raw sewage is also discharged in high volumes, were assayed as a positive control. No evidence of SARS-CoV-2 RNA or infectious virus was found in UK samples, in contrast to RNA positive samples from Serbia. Furthermore, this study shows that infectious SARS-CoV-2 inoculum is stable in Thames water and sediment for <3 days, while SARS-CoV-2 RNA is detectable for at least seven days. This indicates that dilution of wastewater likely limits environmental transmission, and that detection of viral RNA alone is not an indication of pathogen spillover.
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Journal articleZess EK, Dagdas YF, Peers E, et al., 2022,
Regressive evolution of an effector following a host jump in the Irish potato famine pathogen lineage.
, PLoS Pathog, Vol: 18In order to infect a new host species, the pathogen must evolve to enhance infection and transmission in the novel environment. Although we often think of evolution as a process of accumulation, it is also a process of loss. Here, we document an example of regressive evolution of an effector activity in the Irish potato famine pathogen (Phytophthora infestans) lineage, providing evidence that a key sequence motif in the effector PexRD54 has degenerated following a host jump. We began by looking at PexRD54 and PexRD54-like sequences from across Phytophthora species. We found that PexRD54 emerged in the common ancestor of Phytophthora clade 1b and 1c species, and further sequence analysis showed that a key functional motif, the C-terminal ATG8-interacting motif (AIM), was also acquired at this point in the lineage. A closer analysis showed that the P. mirabilis PexRD54 (PmPexRD54) AIM is atypical, the otherwise-conserved central residue mutated from a glutamate to a lysine. We aimed to determine whether this PmPexRD54 AIM polymorphism represented an adaptation to the Mirabilis jalapa host environment. We began by characterizing the M. jalapa ATG8 family, finding that they have a unique evolutionary history compared to previously characterized ATG8s. Then, using co-immunoprecipitation and isothermal titration calorimetry assays, we showed that both full-length PmPexRD54 and the PmPexRD54 AIM peptide bind weakly to the M. jalapa ATG8s. Through a combination of binding assays and structural modelling, we showed that the identity of the residue at the position of the PmPexRD54 AIM polymorphism can underpin high-affinity binding to plant ATG8s. Finally, we conclude that the functionality of the PexRD54 AIM was lost in the P. mirabilis lineage, perhaps owing to as-yet-unknown selection pressure on this effector in the new host environment.
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Journal articleLangley J, Purchase R, Viola S, et al., 2022,
Simulating the low-temperature, metastable electrochromism of Photosystem I: Applications to Thermosynechococcus vulcanus and Chroococcidiopsis thermalis
, JOURNAL OF CHEMICAL PHYSICS, Vol: 157, ISSN: 0021-9606 -
Journal articleIbrahim T, Khandare V, Mirkin FG, et al., 2022,
AF2-multimer guided high accuracy prediction of typical and atypical ATG8 binding motifs
<jats:title>Abstract</jats:title><jats:p>Macroautophagy/autophagy is an intracellular degradation process central to cellular homeostasis and defense against pathogens in eukaryotic cells. Regulation of autophagy relies on hierarchical binding of autophagy cargo receptors and adaptors to ATG8/LC3 protein family members. Interactions with ATG8/LC3 are typically facilitated by a conserved, short linear sequence, referred to as the ATG8/LC3 interacting motif/region (AIM/LIR), present in autophagy adaptors and receptors as well as pathogen virulence factors targeting host autophagy machinery. Since the canonical AIM/LIR sequence can be found in many proteins, identifying functional AIM/LIR motifs has proven challenging. Here we show that protein modelling using Alphafold-Multimer (AF2-multimer) identifies both canonical and atypical AIM/LIR motifs with a high level of accuracy. AF2-multimer can be modified to detect additional functional AIM/LIR motifs by using protein sequences with mutations in primary AIM/LIR residues. By combining protein modelling data from AF2-multimer with phylogenetic analysis of protein sequences and protein-protein interaction assays, we demonstrate that AF2-multimer predicts the physiologically relevant AIM motif in the ATG8-interacting protein 2 (ATI-2) as well as the previously uncharacterized non-canonical AIM motif in ATG3 from potato (<jats:italic>Solanum tuberosum</jats:italic>). AF2-multimer also identified the AIM/LIR motifs in pathogen-encoded virulence factors that target ATG8 members in their plant and human hosts, revealing that cross-kingdom ATG8-LIR/AIM associations can also be predicted by AF2-multimer. We conclude that the AF2-guided discovery of autophagy adaptors/receptors will substantially accelerate our understanding of the molecular basis of autophagy in all biological kingdoms.</jats:p>
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Journal articleHoermann A, Habtewold T, Selvaraj P, et al., 2022,
Gene drive mosquitoes can aid malaria elimination by retarding Plasmodium sporogonic development.
, Sci Adv, Vol: 8Gene drives hold promise for the genetic control of malaria vectors. The development of vector population modification strategies hinges on the availability of effector mechanisms impeding parasite development in transgenic mosquitoes. We augmented a midgut gene of the malaria mosquito Anopheles gambiae to secrete two exogenous antimicrobial peptides, magainin 2 and melittin. This small genetic modification, capable of efficient nonautonomous gene drive, hampers oocyst development in both Plasmodium falciparum and Plasmodium berghei. It delays the release of infectious sporozoites, while it simultaneously reduces the life span of homozygous female transgenic mosquitoes. Modeling the spread of this modification using a large-scale agent-based model of malaria epidemiology reveals that it can break the cycle of disease transmission across a range of transmission intensities.
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Journal articleWong JLC, David S, Sanchez-Garrido J, et al., 2022,
Recurrent emergence of Klebsiella pneumoniae carbapenem resistance mediated by an inhibitory ompK36 mRNA secondary structure.
, Proc Natl Acad Sci U S A, Vol: 119Outer membrane porins in Gram-negative bacteria facilitate antibiotic influx. In Klebsiella pneumoniae, modifications in the porin OmpK36 are implicated in increasing resistance to carbapenems. An analysis of large K. pneumoniae genome collections, encompassing major healthcare-associated clones, revealed the recurrent emergence of a synonymous cytosine-to-thymine transition at position 25 (25c > t) in ompK36. We show that the 25c > t transition increases carbapenem resistance through depletion of OmpK36 from the outer membrane. The mutation attenuates K. pneumoniae in a murine pneumonia model, which accounts for its limited clonal expansion observed by phylogenetic analysis. However, in the context of carbapenem treatment, the 25c > t transition tips the balance toward treatment failure, thus accounting for its recurrent emergence. Mechanistically, the 25c > t transition mediates an intramolecular messenger RNA (mRNA) interaction between a uracil encoded by 25t and the first adenine within the Shine-Dalgarno sequence. This specific interaction leads to the formation of an RNA stem structure, which obscures the ribosomal binding site thus disrupting translation. While mutations reducing OmpK36 expression via transcriptional silencing are known, we uniquely demonstrate the repeated selection of a synonymous ompK36 mutation mediating translational suppression in response to antibiotic pressure.
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Journal articleMatthews TJ, Wayman JP, Cardoso P, et al., 2022,
Threatened and extinct island endemic birds of the world: Distribution, threats and functional diversity
, JOURNAL OF BIOGEOGRAPHY, Vol: 49, Pages: 1920-1940, ISSN: 0305-0270 -
Journal articleChen JM, Wang R, Liu Y, et al., 2022,
Global datasets of leaf photosynthetic capacity for ecological and earth system research
, EARTH SYSTEM SCIENCE DATA, Vol: 14, Pages: 4077-4093, ISSN: 1866-3508 -
Journal articleVincent CM, Beckwith EJ, Simoes da Silva CJ, et al., 2022,
Infection increases activity via Toll dependent and independent mechanisms in Drosophila melanogaster.
, PLoS Pathog, Vol: 18Host behavioural changes are among the most apparent effects of infection. 'Sickness behaviour' can involve a variety of symptoms, including anorexia, depression, and changed activity levels. Here, using a real-time tracking and behavioural profiling platform, we show that in Drosophila melanogaster, several systemic bacterial infections cause significant increases in physical activity, and that the extent of this activity increase is a predictor of survival time in some lethal infections. Using multiple bacteria and D. melanogaster immune and activity mutants, we show that increased activity is driven by at least two different mechanisms. Increased activity after infection with Micrococcus luteus, a Gram-positive bacterium rapidly cleared by the immune response, strictly requires the Toll ligand spätzle. In contrast, increased activity after infection with Francisella novicida, a Gram-negative bacterium that cannot be cleared by the immune response, is entirely independent of both Toll and the parallel IMD pathway. The existence of multiple signalling mechanisms by which bacterial infections drive increases in physical activity implies that this effect may be an important aspect of the host response.
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Journal articleLiu M, Prentice IC, Menviel L, et al., 2022,
Past rapid warmings as a constraint on greenhouse-gas climate feedbacks
, COMMUNICATIONS EARTH & ENVIRONMENT, Vol: 3 -
Journal articleHamilton C, Olona A, Leishman S, et al., 2022,
NLRP3 Inflammasome Priming and Activation Are Regulated by a Phosphatidylinositol-Dependent Mechanism.
, Immunohorizons, Vol: 6, Pages: 642-659Imbalance in lipid homeostasis is associated with discrepancies in immune signaling and is tightly linked to metabolic disorders. The diverse ways in which lipids impact immune signaling, however, remain ambiguous. The phospholipid phosphatidylinositol (PI), which is implicated in numerous immune disorders, is chiefly defined by its phosphorylation status. By contrast, the significance of the two fatty acid chains attached to the PI remains unknown. In this study, by using a mass spectrometry-based assay, we demonstrate a role for PI acyl group chains in regulating both the priming and activation steps of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in mouse macrophages. In response to NLRP3 stimuli, cells deficient in ABC transporter ATP Binding Cassette Subfamily B Member 1 (ABCB1), which effluxes lipid derivatives, revealed defective inflammasome activation. Mechanistically, Abcb1 deficiency shifted the total PI configuration exhibiting a reduced ratio of short-chain to long-chain PI acyl lipids. Consequently, Abcb1 deficiency initiated the rapid degradation of Toll/IL-1R domain-containing adaptor protein, the TLR adaptor protein that binds PI (4,5)-bisphosphate, resulting in defective TLR-dependent signaling, and thus NLRP3 expression. Moreover, this accompanied increased NLRP3 phosphorylation at the Ser291 position and contributed to blunted inflammasome activation. Exogenously supplementing wild-type cells with linoleic acid (LA), but not arachidonic acid, reconfigured PI acyl chains. Accordingly, LA supplementation increased Toll/IL-1R domain-containing adaptor protein degradation, elevated NLRP3 phosphorylation, and abrogated inflammasome activation. Furthermore, NLRP3 Ser291 phosphorylation was dependent on PGE2-induced protein kinase A signaling because pharmacological inhibition of this pathway in LA-enriched cells dephosphorylated NLRP3. Altogether, our study reveals, to our knowledge, a novel metabolic-inflammatory circuit
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