Abstract:
:The most common cystic fibrosis (CF) causing mutation, deletion of phenylalanine 508 (ΔF508 or Phe508del), results in functional expression defect of the CF transmembrane conductance regulator (CFTR) at the apical plasma membrane (PM) of secretory epithelia, which is attributed to the degradation of the misfolded channel at the endoplasmic reticulum (ER). Deletion of phenylalanine 670 (ΔF670) in the yeast oligomycin resistance 1 gene (YOR1, an ABC transporter) of Saccharomyces cerevisiae phenocopies the ΔF508-CFTR folding and trafficking defects. Genome-wide phenotypic (phenomic) analysis of the Yor1-ΔF670 biogenesis identified several modifier genes of mRNA processing and translation, which conferred oligomycin resistance to yeast. Silencing of orthologues of these candidate genes enhanced the ΔF508-CFTR functional expression at the apical PM in human CF bronchial epithelia. Although knockdown of RPL12, a component of the ribosomal stalk, attenuated the translational elongation rate, it increased the folding efficiency as well as the conformational stability of the ΔF508-CFTR, manifesting in 3-fold augmented PM density and function of the mutant. Combination of RPL12 knockdown with the corrector drug, VX-809 (lumacaftor) restored the mutant function to ~50% of the wild-type channel in primary CFTRΔF508/ΔF508 human bronchial epithelia. These results and the observation that silencing of other ribosomal stalk proteins partially rescue the loss-of-function phenotype of ΔF508-CFTR suggest that the ribosomal stalk modulates the folding efficiency of the mutant and is a potential therapeutic target for correction of the ΔF508-CFTR folding defect.
journal_name
PLoS Bioljournal_title
PLoS biologyauthors
Veit G,Oliver K,Apaja PM,Perdomo D,Bidaud-Meynard A,Lin ST,Guo J,Icyuz M,Sorscher EJ,Hartman JL IV,Lukacs GLdoi
10.1371/journal.pbio.1002462subject
Has Abstractpub_date
2016-05-11 00:00:00pages
e1002462issue
5eissn
1544-9173issn
1545-7885pii
PBIOLOGY-D-15-03190journal_volume
14pub_type
杂志文章相关文献
PLOS BIOLOGY文献大全abstract::Pseudomonas aeruginosa is an opportunistic pathogen that often infects open wounds or patients with cystic fibrosis. Once established, P. aeruginosa infections are notoriously difficult to eradicate. This difficulty is in part due to the ability of P. aeruginosa to tolerate antibiotic treatment at the individual-cell ...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.3000573
更新日期:2019-12-16 00:00:00
abstract::As a result of sex chromosome differentiation from ancestral autosomes, male mammalian cells only contain one X chromosome. It has long been hypothesized that X-linked gene expression levels have become doubled in males to restore the original transcriptional output, and that the resulting X overexpression in females ...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.1001328
更新日期:2012-01-01 00:00:00
abstract::Members of the highly conserved class of BEACH domain containing proteins (BDCPs) have been established as broad facilitators of protein-protein interactions and membrane dynamics in the context of human diseases like albinism, bleeding diathesis, impaired cellular immunity, cancer predisposition, and neurological dys...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.1002188
更新日期:2015-07-02 00:00:00
abstract::Every year, ovarian cancer kills approximately 14,000 women in the United States and more than 140,000 women worldwide. Most of these deaths are caused by tumors of the serous histological type, which is rarely diagnosed before it has disseminated. By deep paired-end sequencing of mRNA from serous ovarian cancers, fol...
journal_title:PLoS biology
pub_type: 杂志文章,多中心研究
doi:10.1371/journal.pbio.1001156
更新日期:2011-09-01 00:00:00
abstract::Obesity is a condition characterized by excess adipose tissue that results from positive energy balance and is the most common metabolic disorder in the industrialized world. The obesity epidemic shows no sign of slowing, and it is increasingly a global problem. Serious clinical problems associated with obesity includ...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.1001436
更新日期:2012-01-01 00:00:00
abstract::Zinc is an essential mineral, but our understanding of its uses in the body is limited. Capitalizing on approaches available in the model system Caenorhabditis elegans, Zhao and colleagues show that zinc transduces a signal that induces sperm to become motile. This is an enigmatic process because sperm in all sexually...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.2006204
更新日期:2018-06-07 00:00:00
abstract::We show that the cyclin-dependent kinase inhibitor 1B (CDKN1B)/p27, previously known as a cell cycle inhibitor, is also localized within mitochondria. The migratory capacity of endothelial cells, which need intact mitochondria, is completely dependent on mitochondrial p27. Mitochondrial p27 improves mitochondrial memb...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.2004408
更新日期:2018-06-21 00:00:00
abstract::There is currently a demand for new highly efficient and specific drugs to treat osteoporosis, a chronic bone disease affecting millions of people worldwide. We have developed a combinatorial strategy for engineering bispecific inhibitors that simultaneously target the unique combination of c-FMS and αvβ3 integrin, wh...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.2002979
更新日期:2018-08-24 00:00:00
abstract::Tumors develop through multiple stages, implicating multiple effectors, but the tools to assess how candidate genes contribute to stepwise tumor progression have been limited. We have developed a novel system in which progression of phenotypes in a mouse model of pancreatic islet cell tumorigenesis can be used to meas...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.0050276
更新日期:2007-10-16 00:00:00
abstract::Asymmetric cell division and apoptosis (programmed cell death) are two fundamental processes that are important for the development and function of multicellular organisms. We have found that the processes of asymmetric cell division and apoptosis can be functionally linked. Specifically, we show that asymmetric cell ...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.0060084
更新日期:2008-04-08 00:00:00
abstract::Hosts are likely to respond to parasitic infections by a combination of resistance (expulsion of pathogens) and tolerance (active mitigation of pathology). Of these strategies, the basis of tolerance in animal hosts is relatively poorly understood, with especially little known about how tolerance is manifested in natu...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.1001901
更新日期:2014-07-08 00:00:00
abstract::Telomerase, a unique reverse transcriptase that specifically extends the ends of linear chromosomes, is up-regulated in the vast majority of cancer cells. Here, we show that an indole nucleotide analog, 5-methylcarboxyl-indolyl-2'-deoxyriboside 5'-triphosphate (5-MeCITP), functions as an inhibitor of telomerase activi...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.3000204
更新日期:2019-04-05 00:00:00
abstract::The cerebellum has been proposed to be a crucial component in the state estimation process that combines information from motor efferent and sensory afferent signals to produce a representation of the current state of the motor system. Such a state estimate of the moving human arm would be expected to be used when the...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.0050316
更新日期:2007-11-01 00:00:00
abstract::Pheromones form an essential chemical language of intraspecific communication in many animals. How olfactory systems recognize pheromonal signals with both sensitivity and specificity is not well understood. An important in vivo paradigm for this process is the detection mechanism of the sex pheromone (Z)-11-octadecen...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.1001546
更新日期:2013-01-01 00:00:00
abstract::The array of vibrissae on a rat's face is the first stage in a high-resolution tactile sensing system. Progressing from rostral to caudal in any vibrissae row results in an increase in whisker length and thickness. This may, in turn, provide a systematic map of separate tactile channels governed by the mechanical prop...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.3000699
更新日期:2020-10-22 00:00:00
abstract::Blood vascular networks in vertebrates are essential to tissue survival. Establishment of a fully functional vasculature is complex and requires a number of steps including vasculogenesis and angiogenesis that are followed by differentiation into specialized vascular tissues (i.e., arteries, veins, and lymphatics) and...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.1002148
更新日期:2015-05-15 00:00:00
abstract::Inorganic arsenic is a carcinogen, and its ingestion through foods such as rice presents a significant risk to human health. Plants chemically reduce arsenate to arsenite. Using genome-wide association (GWA) mapping of loci controlling natural variation in arsenic accumulation in Arabidopsis thaliana allowed us to ide...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.1002009
更新日期:2014-12-02 00:00:00
abstract::Catch-up growth after insults to growing organs is paramount to achieving robust body proportions. In fly larvae, injury to individual tissues is followed by local and systemic compensatory mechanisms that allow the damaged tissue to regain normal proportions with other tissues. In vertebrates, local catch-up growth h...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.2005086
更新日期:2018-06-26 00:00:00
abstract::Adaptive evolution is generally assumed to progress through the accumulation of beneficial mutations. However, as deleterious mutations are common in natural populations, they generate a strong selection pressure to mitigate their detrimental effects through compensatory genetic changes. This process can potentially i...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.1001935
更新日期:2014-08-26 00:00:00
abstract::Copper (Cu) has emerged as an important modifier of body lipid metabolism. However, how Cu contributes to the physiology of fat cells remains largely unknown. We found that adipocytes require Cu to establish a balance between main metabolic fuels. Differentiating adipocytes increase their Cu uptake along with the ATP7...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.2006519
更新日期:2018-09-10 00:00:00
abstract::Mitochondrial complex I, the largest and most complicated proton pump of the respiratory chain, links the electron transfer from NADH to ubiquinone to the pumping of four protons from the matrix into the intermembrane space. In humans, defects in complex I are involved in a wide range of degenerative disorders. Recent...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.1001128
更新日期:2011-08-01 00:00:00
abstract::Meta-research is the study of research itself: its methods, reporting, reproducibility, evaluation, and incentives. Given that science is the key driver of human progress, improving the efficiency of scientific investigation and yielding more credible and more useful research results can translate to major benefits. T...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.2005468
更新日期:2018-03-13 00:00:00
abstract::The translocation of single-stranded DNA (ssDNA) across membranes of two cells is a fundamental biological process occurring in both bacterial conjugation and Agrobacterium pathogenesis. Whereas bacterial conjugation spreads antibiotic resistance, Agrobacterium facilitates efficient interkingdom transfer of ssDNA from...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.0060044
更新日期:2008-02-01 00:00:00
abstract::Disease-associated misfolded proteins or proteins damaged due to cellular stress are generally disposed via the cellular protein quality-control system. However, under saturating conditions, misfolded proteins will aggregate. In higher eukaryotes, these aggregates can be transported to accumulate in aggresomes at the ...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.0040417
更新日期:2006-12-01 00:00:00
abstract::Lymphoid T-zone fibroblastic reticular cells (FRCs) actively promote T-cell trafficking, homeostasis, and expansion but can also attenuate excessive T-cell responses via inducible nitric oxide (NO) and constitutive prostanoid release. It remains unclear how these FRC-derived mediators dampen T-cell responses and wheth...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.3000072
更新日期:2019-07-15 00:00:00
abstract::Unc-51-like autophagy activating kinase 1 (ULK1)-autophagy-related 13 (ATG13) is the most upstream autophagy initiation complex that is phosphorylated by mammalian target-of-rapamycin complex 1 (mTORC1) and AMP-activated protein kinase (AMPK) to induce autophagy in asynchronous conditions. However, their phospho-regul...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.3000288
更新日期:2020-06-09 00:00:00
abstract::Contemporary science thrives on collaborative networks, but these can also be found elsewhere in the history of science in unexpected places. When Mendel turned his attention to inheritance in peas he was not an isolated monk, but rather the latest in a line of Moravian researchers and agriculturalists who had been th...
journal_title:PLoS biology
pub_type: 历史文章,杂志文章
doi:10.1371/journal.pbio.1001772
更新日期:2014-01-01 00:00:00
abstract::The maintenance of pluripotency and specification of cellular lineages during embryonic development are controlled by transcriptional regulatory networks, which coordinate specific sets of genes through both activation and repression. The transcriptional repressor RE1-silencing transcription factor (REST) plays import...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.0060256
更新日期:2008-10-28 00:00:00
abstract::DNA microarray analysis of gene expression in steady-state chemostat cultures limited for potassium revealed a surprising connection between potassium and ammonium: potassium limits growth only when ammonium is the nitrogen source. Under potassium limitation, ammonium appears to be toxic for Saccharomyces cerevisiae. ...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.0040351
更新日期:2006-10-01 00:00:00
abstract::Three-dimensional (3D) structural information on many length scales is of central importance in biological research. Excellent methods exist to obtain structures of molecules at atomic, organelles at electron microscopic, and tissue at light-microscopic resolution. A gap exists, however, when 3D tissue structure needs...
journal_title:PLoS biology
pub_type: 杂志文章
doi:10.1371/journal.pbio.0020329
更新日期:2004-11-01 00:00:00