Abstract:
:Cystic Fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR-mediated chloride and bicarbonate transport, with dysregulation of epithelial sodium channels (ENaC). These changes alter fluid and electrolyte homeostasis and result in an exaggerated proinflammatory response driven, in part, by infection. We tested the hypothesis that NLRP3 inflammasome activation and ENaC upregulation drives exaggerated innate-immune responses in this multisystem disease. We identify an enhanced proinflammatory signature, as evidenced by increased levels of IL-18, IL-1β, caspase-1 activity and ASC-speck release in monocytes, epithelia and serum with CF-associated mutations; these differences were reversed by pretreatment with NLRP3 inflammasome inhibitors and notably, inhibition of amiloride-sensitive sodium (Na+) channels. Overexpression of β-ENaC, in the absence of CFTR dysfunction, increased NLRP3-mediated inflammation, indicating that dysregulated, ENaC-dependent signalling may drive exaggerated inflammatory responses in CF. These data support a role for sodium in modulating NLRP3 inflammasome activation.
journal_name
Elifejournal_title
eLifeauthors
Scambler T,Jarosz-Griffiths HH,Lara-Reyna S,Pathak S,Wong C,Holbrook J,Martinon F,Savic S,Peckham D,McDermott MFdoi
10.7554/eLife.49248subject
Has Abstractpub_date
2019-09-18 00:00:00issn
2050-084Xpii
49248journal_volume
8pub_type
杂志文章相关文献
eLife文献大全abstract::Postmitotic tissues are incapable of replacing damaged cells through proliferation, but need to rely on buffering mechanisms to prevent tissue disintegration. By constitutively activating the Ras/MAPK-pathway via RasV12-overexpression in the postmitotic salivary glands of Drosophila larvae, we overrode the glands adap...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.64919
更新日期:2020-12-30 00:00:00
abstract::Psychological theories of suicide suggest that certain traits may reduce aversion to physical threat and increase the probability of transitioning from suicidal ideation to action. Here, we investigated whether blunted sensitivity to bodily signals is associated with suicidal action by comparing individuals with a his...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.51593
更新日期:2020-04-07 00:00:00
abstract::Cell-cell communication in multicellular organisms depends on the dynamic and reversible phosphorylation of protein tyrosine residues. The receptor-linked protein tyrosine phosphatases (RPTPs) receive cues from the extracellular environment and are well placed to influence cell signaling. However, the direct events do...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.44597
更新日期:2019-03-29 00:00:00
abstract::Down syndrome (DS) results in various degrees of cognitive deficits. In DS mouse models, recovery of behavioral and neurophysiological deficits using GABAAR antagonists led to hypothesize an excessive activity of inhibitory circuits in this condition. Nonetheless, whether over-inhibition is present in DS and whether t...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.58731
更新日期:2020-08-12 00:00:00
abstract::Previously, we identified ISRIB as a potent inhibitor of the integrated stress response (ISR) and showed that ISRIB makes cells resistant to the effects of eIF2α phosphorylation and enhances long-term memory in rodents (Sidrauski et al., 2013). Here, we show by genome-wide in vivo ribosome profiling that translation o...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.05033
更新日期:2015-02-26 00:00:00
abstract::India comprises much of the persisting global childhood measles mortality. India implemented a mass second-dose measles immunization campaign in 2010. We used interrupted time series and multilevel regression to quantify the campaign's impact on measles mortality using the nationally representative Million Death Study...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.43290
更新日期:2019-03-05 00:00:00
abstract::During cell locomotion and endocytosis, membrane-tethered WASP proteins stimulate actin filament nucleation by the Arp2/3 complex. This process generates highly branched arrays of filaments that grow toward the membrane to which they are tethered, a conflict that seemingly would restrict filament growth. Using three-c...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.01008
更新日期:2013-09-03 00:00:00
abstract::Yeast cells undergoing the diauxic response show a striking upstream shift in poly(A) site utilization, with increased use of ORF-proximal poly(A) sites resulting in shorter 3' mRNA isoforms for most genes. This altered poly(A) pattern is extremely similar to that observed in cells containing Pol II derivatives with s...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.59810
更新日期:2020-08-26 00:00:00
abstract::Baboons, members of the genus Papio, comprise six closely related species distributed throughout sub-Saharan Africa and southwest Arabia. The species exhibit more ecological flexibility and a wider range of social systems than many other primates. This article summarizes our current knowledge of the natural history of...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.50989
更新日期:2019-11-12 00:00:00
abstract::B-cell receptors form ordered clusters to recruit kinases and exclude phosphatases. ...
journal_title:eLife
pub_type: 评论,杂志文章
doi:10.7554/eLife.25375
更新日期:2017-03-30 00:00:00
abstract::Sex-optimal diets have different effects on gene expression in female and male flies. ...
journal_title:eLife
pub_type: 评论,杂志文章
doi:10.7554/eLife.51289
更新日期:2019-10-01 00:00:00
abstract::WNK1, a kinase that controls kidney salt homeostasis, also regulates adhesion and migration in CD4+ T cells. Wnk1 is highly expressed in thymocytes, and since migration is important for thymocyte maturation, we investigated a role for WNK1 in mouse thymocyte development. We find that WNK1 is required for the transitio...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.56934
更新日期:2020-10-14 00:00:00
abstract::AKT is implicated in neurological disorders. AKT has three isoforms, AKT1/AKT2/AKT3, with brain cell type-specific expression that may differentially influence behavior. Therefore, we examined single Akt isoform, conditional brain-specific Akt1, and double Akt1/3 mutant mice in behaviors relevant to neuropsychiatric d...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.56630
更新日期:2020-12-16 00:00:00
abstract::We recently reported that the C2AB portion of Synaptotagmin 1 (Syt1) could self-assemble into Ca(2+)-sensitive ring-like oligomers on membranes, which could potentially regulate neurotransmitter release. Here we report that analogous ring-like oligomers assemble from the C2AB domains of other Syt isoforms (Syt2, Syt7,...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.17262
更新日期:2016-07-19 00:00:00
abstract::Dorsal/ventral (DV) patterning of the sea urchin embryo relies on a ventrally-localized organizer expressing Nodal, a pivotal regulator of the DV gene regulatory network. However, the inceptive mechanisms imposing the symmetry-breaking are incompletely understood. In Paracentrotus lividus, the Hbox12 homeodomain-conta...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.04664
更新日期:2014-12-02 00:00:00
abstract::Human SEMAPHORIN 5A (SEMA5A) is an autism susceptibility gene; however, its function in brain development is unknown. In this study, we show that mouse Sema5A negatively regulates synaptogenesis in early, developmentally born, hippocampal dentate granule cells (GCs). Sema5A is strongly expressed by GCs and regulates d...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.04390
更新日期:2014-10-14 00:00:00
abstract::Membrane transporters of the RND superfamily confer multidrug resistance to pathogenic bacteria, and are essential for cholesterol metabolism and embryonic development in humans. We use high-resolution X-ray crystallography and computational methods to delineate the mechanism of the homotrimeric RND-type proton/drug a...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.03145
更新日期:2014-09-19 00:00:00
abstract::Vesicle fusion is mediated by an assembly of SNARE proteins between opposing membranes, but it is unknown whether transmembrane domains (TMDs) of SNARE proteins serve mechanistic functions that go beyond passive anchoring of the force-generating SNAREpin to the fusing membranes. Here, we show that conformational flexi...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.17571
更新日期:2016-06-25 00:00:00
abstract::Apical constriction is a widely utilized cell shape change linked to folding, bending and invagination of polarized epithelia. It remains unclear how apical constriction is regulated spatiotemporally during tissue invagination and how this cellular process contributes to tube formation in different developmental conte...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.22235
更新日期:2017-03-06 00:00:00
abstract::The interferon-inducible transmembrane (IFITM) proteins belong to the Dispanin/CD225 family and inhibit diverse virus infections. IFITM3 reduces membrane fusion between cells and virions through a poorly characterized mechanism. Mutation of proline-rich transmembrane protein 2 (PRRT2), a regulator of neurotransmitter ...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.58537
更新日期:2020-10-28 00:00:00
abstract::Uropathogenic E. coli (UPEC), which cause urinary tract infections (UTI), utilize type 1 pili, a chaperone usher pathway (CUP) pilus, to cause UTI and colonize the gut. The pilus rod, comprised of repeating FimA subunits, provides a structural scaffold for displaying the tip adhesin, FimH. We solved the 4.2 Å resoluti...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.31662
更新日期:2018-01-18 00:00:00
abstract::One of the major unanswered questions in evolutionary biology is when and how the transition between diderm (two membranes) and monoderm (one membrane) cell envelopes occurred in Bacteria. The Negativicutes and the Halanaerobiales belong to the classically monoderm Firmicutes, but possess outer membranes with lipopoly...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.14589
更新日期:2016-08-31 00:00:00
abstract::Many primary sensory cilia exhibit unique architectures that are critical for transduction of specific sensory stimuli. Although basic ciliogenic mechanisms are well described, how complex ciliary structures are generated remains unclear. Seminal work performed several decades ago provided an initial but incomplete de...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.01948
更新日期:2014-03-25 00:00:00
abstract::CRISPR-based homing gene drives have sparked both enthusiasm and deep concerns due to their potential for genetically altering entire species. This raises the question about our ability to prevent the unintended spread of such drives from the laboratory into a natural population. Here, we experimentally demonstrate th...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.41439
更新日期:2019-01-22 00:00:00
abstract::Mechanisms of the neural circuits that guide mating decisions in male flies are becoming clearer. ...
journal_title:eLife
pub_type: 评论,杂志文章
doi:10.7554/eLife.13093
更新日期:2015-12-23 00:00:00
abstract::The factors that govern assembly of the gut microbiota are insufficiently understood. Here, we test the hypothesis that inter-individual microbiota variation can arise solely from differences in the order and timing by which the gut is colonized early in life. Experiments in which mice were inoculated in sequence eith...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.36521
更新日期:2018-09-18 00:00:00
abstract::Altered insulin signaling has been linked to widespread nervous system dysfunction including cognitive dysfunction, neuropathy and susceptibility to neurodegenerative disease. However, knowledge of the cellular mechanisms underlying the effects of insulin on neuronal function is incomplete. Here, we show that cell aut...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.16807
更新日期:2016-08-15 00:00:00
abstract::Mood and anxiety disorders are the most prevalent psychiatric conditions and are exacerbated by stress. Recent studies have suggested cyclooxygenase-2 (COX-2) inhibition could represent a novel treatment approach or augmentation strategy for affective disorders including anxiety disorders and major depression. We show...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.14137
更新日期:2016-05-10 00:00:00
abstract::The number of ions required to drive substrate transport through a secondary active transporter determines the protein's ability to create a substrate gradient, a feature essential to its physiological function, and places fundamental constraints on the transporter's mechanism. Stoichiometry is known for a wide array ...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.21016
更新日期:2017-01-25 00:00:00
abstract::Lamina-associated polypeptide 1 (LAP1) resides at the nuclear envelope and interacts with Torsins, poorly understood endoplasmic reticulum (ER)-localized AAA+ ATPases, through a conserved, perinuclear domain. We determined the crystal structure of the perinuclear domain of human LAP1. LAP1 possesses an atypical AAA+ f...
journal_title:eLife
pub_type: 杂志文章
doi:10.7554/eLife.03239
更新日期:2014-08-22 00:00:00