Journals

Leaky resistance and the conditions for the existence of lytic bacteriophage

PLOS Biology (new articles) - 5 hours 29 min назад

by Waqas N. Chaudhry, Maroš Pleška, Nilang N. Shah, Howard Weiss, Ingrid C. McCall, Justin R. Meyer, Animesh Gupta, Călin C. Guet, Bruce R. Levin

In experimental cultures, when bacteria are mixed with lytic (virulent) bacteriophage, bacterial cells resistant to the phage commonly emerge and become the dominant population of bacteria. Following the ascent of resistant mutants, the densities of bacteria in these simple communities become limited by resources rather than the phage. Despite the evolution of resistant hosts, upon which the phage cannot replicate, the lytic phage population is most commonly maintained in an apparently stable state with the resistant bacteria. Several mechanisms have been put forward to account for this result. Here we report the results of population dynamic/evolution experiments with a virulent mutant of phage Lambda, λVIR, and Escherichia coli in serial transfer cultures. We show that, following the ascent of λVIR-resistant bacteria, λVIR is maintained in the majority of cases in maltose-limited minimal media and in all cases in nutrient-rich broth. Using mathematical models and experiments, we show that the dominant mechanism responsible for maintenance of λVIR in these resource-limited populations dominated by resistant E. coli is a high rate of either phenotypic or genetic transition from resistance to susceptibility—a hitherto undemonstrated mechanism we term "leaky resistance." We discuss the implications of leaky resistance to our understanding of the conditions for the maintenance of phage in populations of bacteria—their “existence conditions.”
Категории: Biology, Journals

Call combinations in birds and the evolution of compositional syntax

PLOS Biology (new articles) - ср, 2018-08-15 23:00

by Toshitaka N. Suzuki, David Wheatcroft, Michael Griesser

Syntax is the set of rules for combining words into phrases, providing the basis for the generative power of linguistic expressions. In human language, the principle of compositionality governs how words are combined into a larger unit, the meaning of which depends on both the meanings of the words and the way in which they are combined. This linguistic capability, i.e., compositional syntax, has long been considered a trait unique to human language. Here, we review recent studies on call combinations in a passerine bird, the Japanese tit (Parus minor), that provide the first firm evidence for compositional syntax in a nonhuman animal. While it has been suggested that the findings of these studies fail to provide evidence for compositionality in Japanese tits, this criticism is based on misunderstanding of experimental design, misrepresentation of the importance of word order in human syntax, and necessitating linguistic capabilities beyond those given by the standard definition of compositionality. We argue that research on avian call combinations has provided the first steps in elucidating how compositional expressions could have emerged in animal communication systems.
Категории: Biology, Journals

Compositionality in animals and humans

PLOS Biology (new articles) - ср, 2018-08-15 23:00

by Simon W. Townsend, Sabrina Engesser, Sabine Stoll, Klaus Zuberbühler, Balthasar Bickel

A key step in understanding the evolution of human language involves unravelling the origins of language’s syntactic structure. One approach seeks to reduce the core of syntax in humans to a single principle of recursive combination, merge, for which there is no evidence in other species. We argue for an alternative approach. We review evidence that beneath the staggering complexity of human syntax, there is an extensive layer of nonproductive, nonhierarchical syntax that can be fruitfully compared to animal call combinations. This is the essential groundwork that must be explored and integrated before we can elucidate, with sufficient precision, what exactly made it possible for human language to explode its syntactic capacity, transitioning from simple nonproductive combinations to the unrivalled complexity that we now have.
Категории: Biology, Journals

Serial representation of items during working memory maintenance at letter-selective cortical sites

PLOS Biology (new articles) - ср, 2018-08-15 23:00

by Ali Bahramisharif, Ole Jensen, Joshua Jacobs, John Lisman

A key component of working memory is the ability to remember multiple items simultaneously. To understand how the human brain maintains multiple items in memory, we examined direct brain recordings of neural oscillations from neurosurgical patients as they performed a working memory task. We analyzed the data to identify the neural representations of individual memory items by identifying recording sites with broadband gamma activity that varied according to the identity of the letter a subject viewed. Next, we tested a previously proposed model of working memory, which had hypothesized that the neural representations of individual memory items sequentially occurred at different phases of the theta/alpha cycle. Consistent with this model, the phase of the theta/alpha oscillation when stimulus-related gamma activity occurred during maintenance reflected the order of list presentation. These results suggest that working memory is organized by a cortical phase code coordinated by coupled theta/alpha and gamma oscillations and, more broadly, provide support for the serial representation of items in working memory.
Категории: Biology, Journals

Why are RNA virus mutation rates so damn high?

PLOS Biology (new articles) - пн, 2018-08-13 23:00

by Siobain Duffy

The high mutation rate of RNA viruses is credited with their evolvability and virulence. This Primer, however, discusses recent evidence that this is, in part, a byproduct of selection for faster genomic replication.
Категории: Biology, Journals

Evolutionary diversification of the HAP2 membrane insertion motifs to drive gamete fusion across eukaryotes

PLOS Biology (new articles) - пн, 2018-08-13 23:00

by Juliette Fedry, Jennifer Forcina, Pierre Legrand, Gérard Péhau-Arnaudet, Ahmed Haouz, Mark Johnson, Felix A. Rey, Thomas Krey

HAPLESS2 (HAP2) is a broadly conserved, gamete-expressed transmembrane protein that was shown recently to be structurally homologous to viral class II fusion proteins, which initiate fusion with host cells via insertion of fusion loops into the host membrane. However, the functional conformation of the HAP2 fusion loops has remained unknown, as the reported X-ray structure of Chlamydomonas reinhardtii HAP2 lacked this critical region. Here, we report a structure-guided alignment that reveals diversification of the proposed HAP2 fusion loops. Representative crystal structures show that in flowering plants, HAP2 has a single prominent fusion loop projecting an amphipathic helix at its apex, while in trypanosomes, three small nonpolar loops of HAP2 are poised to interact with the target membrane. A detailed structure-function analysis of the Arabidopsis HAP2 amphipathic fusion helix defines key residues that are essential for membrane insertion and for gamete fusion. Our study suggests that HAP2 may have evolved multiple modes of membrane insertion to accommodate the diversity of membrane environments it has encountered during eukaryotic evolution.
Категории: Biology, Journals

Provenance and risk in transfer of biological materials

PLOS Biology (new articles) - пн, 2018-08-13 23:00

by Jane Nielsen, Tania Bubela, Don R. C. Chalmers, Amber Johns, Linda Kahl, Joanne Kamens, Charles Lawson, John Liddicoat, Rebekah McWhirter, Ann Monotti, James Scheibner, Tess Whitton, Dianne Nicol

Whereas biological materials were once transferred freely, there has been a marked shift in the formalisation of exchanges involving these materials, primarily through the use of Material Transfer Agreements (MTAs). This paper considers how risk aversion dominates MTA negotiations and the impact it may have on scientific progress. Risk aversion is often based on unwarranted fears of incurring liability through the use of a material or loss of control or missing out on commercialisation opportunities. Evidence to date has suggested that complexity tends to permeate even straightforward transactions despite extensive efforts to implement simple, standard MTAs. We argue that in most cases, MTAs need do little more than establish provenance, and any attempt to extend MTAs beyond this simple function constitutes stifling behaviour. Drawing on available examples of favourable practice, we point to a number of strategies that may usefully be employed to reduce risk-averse tendencies, including the promotion of simplicity, education of those engaged in the MTA process, and achieving a cultural shift in the way in which technology transfer office (TTO) success is measured in institutions employing MTAs.
Категории: Biology, Journals

Heterogeneity and longevity of antibody memory to viruses and vaccines

PLOS Biology (new articles) - пт, 2018-08-10 23:00

by Alice Antia, Hasan Ahmed, Andreas Handel, Nichole E. Carlson, Ian J. Amanna, Rustom Antia, Mark Slifka

Determining the duration of protective immunity requires quantifying the magnitude and rate of loss of antibodies to different virus and vaccine antigens. A key complication is heterogeneity in both the magnitude and decay rate of responses of different individuals to a given vaccine, as well as of a given individual to different vaccines. We analyzed longitudinal data on antibody titers in 45 individuals to characterize the extent of this heterogeneity and used models to determine how it affected the longevity of protective immunity to measles, rubella, vaccinia, tetanus, and diphtheria. Our analysis showed that the magnitude of responses in different individuals varied between 12- and 200-fold (95% coverage) depending on the antigen. Heterogeneity in the magnitude and decay rate contribute comparably to variation in the longevity of protective immunity between different individuals. We found that some individuals have, on average, slightly longer-lasting memory than others—on average, they have higher antibody levels with slower decay rates. We identified different patterns for the loss of protective levels of antibodies to different vaccine and virus antigens. Specifically, we found that for the first 25 to 50 years, virtually all individuals have protective antibody titers against diphtheria and tetanus, respectively, but about 10% of the population subsequently lose protective immunity per decade. In contrast, at the outset, not all individuals had protective titers against measles, rubella, and vaccinia. However, these antibody titers wane much more slowly, with a loss of protective immunity in only 1% to 3% of the population per decade. Our results highlight the importance of long-term longitudinal studies for estimating the duration of protective immunity and suggest both how vaccines might be improved and how boosting schedules might be reevaluated.
Категории: Biology, Journals

A non-cell-autonomous actin redistribution enables isotropic retinal growth

PLOS Biology (new articles) - пт, 2018-08-10 23:00

by Marija Matejčić, Guillaume Salbreux, Caren Norden

Tissue shape is often established early in development and needs to be scaled isotropically during growth. However, the cellular contributors and ways by which cells interact tissue-wide to enable coordinated isotropic tissue scaling are not yet understood. Here, we follow cell and tissue shape changes in the zebrafish retinal neuroepithelium, which forms a cup with a smooth surface early in development and maintains this architecture as it grows. By combining 3D analysis and theory, we show how a global increase in cell height can maintain tissue shape during growth. Timely cell height increase occurs concurrently with a non-cell-autonomous actin redistribution. Blocking actin redistribution and cell height increase perturbs isotropic scaling and leads to disturbed, folded tissue shape. Taken together, our data show how global changes in cell shape enable isotropic growth of the developing retinal neuroepithelium, a concept that could also apply to other systems.
Категории: Biology, Journals

Transcriptional programming of lipid and amino acid metabolism by the skeletal muscle circadian clock

PLOS Biology (new articles) - пт, 2018-08-10 23:00

by Kenneth Allen Dyar, Michaël Jean Hubert, Ashfaq Ali Mir, Stefano Ciciliot, Dominik Lutter, Franziska Greulich, Fabiana Quagliarini, Maximilian Kleinert, Katrin Fischer, Thomas Oliver Eichmann, Lauren Emily Wright, Marcia Ivonne Peña Paz, Alberto Casarin, Vanessa Pertegato, Vanina Romanello, Mattia Albiero, Sara Mazzucco, Rosario Rizzuto, Leonardo Salviati, Gianni Biolo, Bert Blaauw, Stefano Schiaffino, N. Henriette Uhlenhaut

Circadian clocks are fundamental physiological regulators of energy homeostasis, but direct transcriptional targets of the muscle clock machinery are unknown. To understand how the muscle clock directs rhythmic metabolism, we determined genome-wide binding of the master clock regulators brain and muscle ARNT-like protein 1 (BMAL1) and REV-ERBα in murine muscles. Integrating occupancy with 24-hr gene expression and metabolomics after muscle-specific loss of BMAL1 and REV-ERBα, here we unravel novel molecular mechanisms connecting muscle clock function to daily cycles of lipid and protein metabolism. Validating BMAL1 and REV-ERBα targets using luciferase assays and in vivo rescue, we demonstrate how a major role of the muscle clock is to promote diurnal cycles of neutral lipid storage while coordinately inhibiting lipid and protein catabolism prior to awakening. This occurs by BMAL1-dependent activation of Dgat2 and REV-ERBα-dependent repression of major targets involved in lipid metabolism and protein turnover (MuRF-1, Atrogin-1). Accordingly, muscle-specific loss of BMAL1 is associated with metabolic inefficiency, impaired muscle triglyceride biosynthesis, and accumulation of bioactive lipids and amino acids. Taken together, our data provide a comprehensive overview of how genomic binding of BMAL1 and REV-ERBα is related to temporal changes in gene expression and metabolite fluctuations.
Категории: Biology, Journals

A systems genetics resource and analysis of sleep regulation in the mouse

PLOS Biology (new articles) - чт, 2018-08-09 23:00

by Shanaz Diessler, Maxime Jan, Yann Emmenegger, Nicolas Guex, Benita Middleton, Debra J. Skene, Mark Ibberson, Frederic Burdet, Lou Götz, Marco Pagni, Martial Sankar, Robin Liechti, Charlotte N. Hor, Ioannis Xenarios, Paul Franken

Sleep is essential for optimal brain functioning and health, but the biological substrates through which sleep delivers these beneficial effects remain largely unknown. We used a systems genetics approach in the BXD genetic reference population (GRP) of mice and assembled a comprehensive experimental knowledge base comprising a deep “sleep-wake” phenome, central and peripheral transcriptomes, and plasma metabolome data, collected under undisturbed baseline conditions and after sleep deprivation (SD). We present analytical tools to interactively interrogate the database, visualize the molecular networks altered by sleep loss, and prioritize candidate genes. We found that a one-time, short disruption of sleep already extensively reshaped the systems genetics landscape by altering 60%–78% of the transcriptomes and the metabolome, with numerous genetic loci affecting the magnitude and direction of change. Systems genetics integrative analyses drawing on all levels of organization imply α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking and fatty acid turnover as substrates of the negative effects of insufficient sleep. Our analyses demonstrate that genetic heterogeneity and the effects of insufficient sleep itself on the transcriptome and metabolome are far more widespread than previously reported.
Категории: Biology, Journals

Long-term all-optical interrogation of cortical neurons in awake-behaving nonhuman primates

PLOS Biology (new articles) - ср, 2018-08-08 23:00

by Niansheng Ju, Rundong Jiang, Stephen L. Macknik, Susana Martinez-Conde, Shiming Tang

Whereas optogenetic techniques have proven successful in their ability to manipulate neuronal populations—with high spatial and temporal fidelity—in species ranging from insects to rodents, significant obstacles remain in their application to nonhuman primates (NHPs). Robust optogenetics-activated behavior and long-term monitoring of target neurons have been challenging in NHPs. Here, we present a method for all-optical interrogation (AOI), integrating optical stimulation and simultaneous two-photon (2P) imaging of neuronal populations in the primary visual cortex (V1) of awake rhesus macaques. A red-shifted channel-rhodopsin transgene (ChR1/VChR1 [C1V1]) and genetically encoded calcium indicators (genetically encoded calmodulin protein [GCaMP]5 or GCaMP6s) were delivered by adeno-associated viruses (AAVs) and subsequently expressed in V1 neuronal populations for months. We achieved optogenetic stimulation using both single-photon (1P) activation of neuronal populations and 2P activation of single cells, while simultaneously recording 2P calcium imaging in awake NHPs. Optogenetic manipulations of V1 neuronal populations produced reliable artificial visual percepts. Together, our advances show the feasibility of precise and stable AOI of cortical neurons in awake NHPs, which may lead to broad applications in high-level cognition and preclinical testing studies.
Категории: Biology, Journals

Nitrogen fixation in a landrace of maize is supported by a mucilage-associated diazotrophic microbiota

PLOS Biology (new articles) - вт, 2018-08-07 23:00

by Allen Van Deynze, Pablo Zamora, Pierre-Marc Delaux, Cristobal Heitmann, Dhileepkumar Jayaraman, Shanmugam Rajasekar, Danielle Graham, Junko Maeda, Donald Gibson, Kevin D. Schwartz, Alison M. Berry, Srijak Bhatnagar, Guillaume Jospin, Aaron Darling, Richard Jeannotte, Javier Lopez, Bart C. Weimer, Jonathan A. Eisen, Howard-Yana Shapiro, Jean-Michel Ané, Alan B. Bennett

Plants are associated with a complex microbiota that contributes to nutrient acquisition, plant growth, and plant defense. Nitrogen-fixing microbial associations are efficient and well characterized in legumes but are limited in cereals, including maize. We studied an indigenous landrace of maize grown in nitrogen-depleted soils in the Sierra Mixe region of Oaxaca, Mexico. This landrace is characterized by the extensive development of aerial roots that secrete a carbohydrate-rich mucilage. Analysis of the mucilage microbiota indicated that it was enriched in taxa for which many known species are diazotrophic, was enriched for homologs of genes encoding nitrogenase subunits, and harbored active nitrogenase activity as assessed by acetylene reduction and 15N2 incorporation assays. Field experiments in Sierra Mixe using 15N natural abundance or 15N-enrichment assessments over 5 years indicated that atmospheric nitrogen fixation contributed 29%–82% of the nitrogen nutrition of Sierra Mixe maize.
Категории: Biology, Journals

The taste of ribonucleosides: Novel macronutrients essential for larval growth are sensed by <i>Drosophila</i> gustatory receptor proteins

PLOS Biology (new articles) - вт, 2018-08-07 23:00

by Dushyant Mishra, Natasha Thorne, Chika Miyamoto, Christopher Jagge, Hubert Amrein

Animals employ various types of taste receptors to identify and discriminate between different nutritious food chemicals. These macronutrients are thought to fall into 3 major groups: carbohydrates/sugars, proteins/amino acids, and fats. Here, we report that Drosophila larvae exhibit a novel appetitive feeding behavior towards ribose, ribonucleosides, and RNA. We identified members of the gustatory receptor (Gr) subfamily 28 (Gr28), expressed in both external and internal chemosensory neurons as molecular receptors necessary for cellular and appetitive behavioral responses to ribonucleosides and RNA. Specifically, behavioral preference assays show that larvae are strongly attracted to ribose- or RNA-containing agarose in a Gr28-dependent manner. Moreover, Ca2+ imaging experiments reveal that Gr28a-expressing taste neurons are activated by ribose, RNA and some ribonucleosides and that these responses can be conveyed to Gr43aGAL4 fructose-sensing neurons by expressing single members of the Gr28 gene family. Lastly, we establish a critical role in behavioral fitness for the Gr28 genes by showing that Gr28 mutant larvae exhibit low survival rates when challenged to find ribonucleosides in food. Together, our work identifies a novel taste modality dedicated to the detection of RNA and ribonucleosides, nutrients that are essential for survival during the accelerated growth phase of Drosophila larvae.
Категории: Biology, Journals

Surf4 (Erv29p) binds amino-terminal tripeptide motifs of soluble cargo proteins with different affinities, enabling prioritization of their exit from the endoplasmic reticulum

PLOS Biology (new articles) - вт, 2018-08-07 23:00

by Ying Yin, Mekka R. Garcia, Alexander J. Novak, Allison M. Saunders, Raira S. Ank, Anna S. Nam, Larry W. Fisher

Some secreted proteins that assemble into large complexes, such as extracellular matrices or hormones and enzymes in storage granules, must be kept at subaggregation concentrations during intracellular trafficking. We show surfeit locus protein 4 (Surf4) is the cargo receptor that establishes different steady-state concentrations for a variety of soluble cargo proteins within the endoplasmic reticulum (ER) through interaction with the amino-terminal tripeptides exposed after removal of leader sequences. We call this motif the ER-Exit by Soluble Cargo using Amino-terminal Peptide-Encoding motif (ER-ESCAPE motif). Proteins that most readily aggregate in the ER lumen (e.g., dentin sialophosphoprotein [DSPP] and amelogenin, X-linked [AMELX]) have strong ER-ESCAPE motifs to inhibit aggregate formation, while less susceptible cargo exhibits weaker motifs. Specific changes in a single amino acid of the tripeptide result in aggregate formation and failure to efficiently traffic cargo out of the ER. A logical subset of 8,000 possible tripeptides starting a model soluble cargo protein (growth hormone) established a continuum of steady-state ER concentrations ranging from low (i.e., high affinity for receptor) to the highest concentrations associated with bulk flow–limited trafficking observed for nonbinding motifs. Human cells lacking Surf4 no longer preferentially trafficked cargo expressing strong ER-ESCAPE motifs. Reexpression of Surf4 or expression of yeast’s ortholog, ER-derived vesicles protein 29 (Erv29p), rescued enhanced ER trafficking in Surf4-null cells. Hence our work describes a new way of preferentially exporting soluble cargo out of the ER that maintains proteins below the concentrations at which they form damaging aggregates.
Категории: Biology, Journals

Representational interactions during audiovisual speech entrainment: Redundancy in left posterior superior temporal gyrus and synergy in left motor cortex

PLOS Biology (new articles) - пн, 2018-08-06 23:00

by Hyojin Park, Robin A. A. Ince, Philippe G. Schyns, Gregor Thut, Joachim Gross

Integration of multimodal sensory information is fundamental to many aspects of human behavior, but the neural mechanisms underlying these processes remain mysterious. For example, during face-to-face communication, we know that the brain integrates dynamic auditory and visual inputs, but we do not yet understand where and how such integration mechanisms support speech comprehension. Here, we quantify representational interactions between dynamic audio and visual speech signals and show that different brain regions exhibit different types of representational interaction. With a novel information theoretic measure, we found that theta (3–7 Hz) oscillations in the posterior superior temporal gyrus/sulcus (pSTG/S) represent auditory and visual inputs redundantly (i.e., represent common features of the two), whereas the same oscillations in left motor and inferior temporal cortex represent the inputs synergistically (i.e., the instantaneous relationship between audio and visual inputs is also represented). Importantly, redundant coding in the left pSTG/S and synergistic coding in the left motor cortex predict behavior—i.e., speech comprehension performance. Our findings therefore demonstrate that processes classically described as integration can have different statistical properties and may reflect distinct mechanisms that occur in different brain regions to support audiovisual speech comprehension.
Категории: Biology, Journals

KDM5 histone demethylases repress immune response via suppression of STING

PLOS Biology (new articles) - пн, 2018-08-06 23:00

by Lizhen Wu, Jian Cao, Wesley L. Cai, Sabine M. Lang, John R. Horton, Daniel J. Jansen, Zongzhi Z. Liu, Jocelyn F. Chen, Meiling Zhang, Bryan T. Mott, Katherine Pohida, Ganesha Rai, Stephen C. Kales, Mark J. Henderson, Xin Hu, Ajit Jadhav, David J. Maloney, Anton Simeonov, Shu Zhu, Akiko Iwasaki, Matthew D. Hall, Xiaodong Cheng, Gerald S. Shadel, Qin Yan

Cyclic GMP-AMP (cGAMP) synthase (cGAS) stimulator of interferon genes (STING) senses pathogen-derived or abnormal self-DNA in the cytosol and triggers an innate immune defense against microbial infection and cancer. STING agonists induce both innate and adaptive immune responses and are a new class of cancer immunotherapy agents tested in multiple clinical trials. However, STING is commonly silenced in cancer cells via unclear mechanisms, limiting the application of these agonists. Here, we report that the expression of STING is epigenetically suppressed by the histone H3K4 lysine demethylases KDM5B and KDM5C and is activated by the opposing H3K4 methyltransferases. The induction of STING expression by KDM5 blockade triggered a robust interferon response in a cytosolic DNA-dependent manner in breast cancer cells. This response resulted in resistance to infection by DNA and RNA viruses. In human tumors, KDM5B expression is inversely associated with STING expression in multiple cancer types, with the level of intratumoral CD8+ T cells, and with patient survival in cancers with a high level of cytosolic DNA, such as human papilloma virus (HPV)-positive head and neck cancer. These results demonstrate a novel epigenetic regulatory pathway of immune response and suggest that KDM5 demethylases are potential targets for antipathogen treatment and anticancer immunotherapy.
Категории: Biology, Journals

The mitochondrial transporter SLC25A25 links ciliary TRPP2 signaling and cellular metabolism

PLOS Biology (new articles) - пн, 2018-08-06 23:00

by Alexis Hofherr, Claudia Seger, Fiona Fitzpatrick, Tilman Busch, Elisabeth Michel, Jingting Luan, Lea Osterried, Frieder Linden, Albrecht Kramer-Zucker, Barbara Wakimoto, Conny Schütze, Nils Wiedemann, Anna Artati, Jerzy Adamski, Gerd Walz, Edmund R. S. Kunji, Craig Montell, Terry Watnick, Michael Köttgen

Cilia are organelles specialized in movement and signal transduction. The ciliary transient receptor potential ion channel polycystin-2 (TRPP2) controls elementary cilia-mediated physiological functions ranging from male fertility and kidney development to left–right patterning. However, the molecular components translating TRPP2 channel–mediated Ca2+ signals into respective physiological functions are unknown. Here, we show that the Ca2+-regulated mitochondrial ATP-Mg/Pi solute carrier 25 A 25 (SLC25A25) acts downstream of TRPP2 in an evolutionarily conserved metabolic signaling pathway. We identify SLC25A25 as an essential component in this cilia-dependent pathway using a genome-wide forward genetic screen in Drosophila melanogaster, followed by a targeted analysis of SLC25A25 function in zebrafish left–right patterning. Our data suggest that TRPP2 ion channels regulate mitochondrial SLC25A25 transporters via Ca2+ establishing an evolutionarily conserved molecular link between ciliary signaling and mitochondrial metabolism.
Категории: Biology, Journals

Centromeric signaling proteins boost G1 cyclin degradation and modulate cell size in budding yeast

PLOS Biology (new articles) - пн, 2018-08-06 23:00

by Joan M. Martínez-Láinez, David F. Moreno, Eva Parisi, Josep Clotet, Martí Aldea

Cell size scales with ploidy in a great range of eukaryotes, but the underlying mechanisms remain unknown. Using various orthogonal single-cell approaches, we show that cell size increases linearly with centromere (CEN) copy number in budding yeast. This effect is due to a G1 delay mediated by increased degradation of Cln3, the most upstream G1 cyclin acting at Start, and specific centromeric signaling proteins, namely Mad3 and Bub3. Mad3 binds both Cln3 and Cdc4, the adaptor component of the Skp1/Cul1/F-box (SCF) complex that targets Cln3 for degradation, these interactions being essential for the CEN-dosage dependent effects on cell size. Our results reveal a pathway that modulates cell size as a function of CEN number, and we speculate that, in cooperation with other CEN-independent mechanisms, it could assist the cell to attain efficient mass/ploidy ratios.
Категории: Biology, Journals

Tissue-specific degradation of essential centrosome components reveals distinct microtubule populations at microtubule organizing centers

PLOS Biology (new articles) - пн, 2018-08-06 23:00

by Maria D. Sallee, Jennifer C. Zonka, Taylor D. Skokan, Brian C. Raftrey, Jessica L. Feldman

Non-centrosomal microtubule organizing centers (ncMTOCs) are found in most differentiated cells, but how these structures regulate microtubule organization and dynamics is largely unknown. We optimized a tissue-specific degradation system to test the role of the essential centrosomal microtubule nucleators γ-tubulin ring complex (γ-TuRC) and AIR-1/Aurora A at the apical ncMTOC, where they both localize in Caenorhabditis elegans embryonic intestinal epithelial cells. As at the centrosome, the core γ-TuRC component GIP-1/GCP3 is required to recruit other γ-TuRC components to the apical ncMTOC, including MZT-1/MZT1, characterized here for the first time in animal development. In contrast, AIR-1 and MZT-1 were specifically required to recruit γ-TuRC to the centrosome, but not to centrioles or to the apical ncMTOC. Surprisingly, microtubules remain robustly organized at the apical ncMTOC upon γ-TuRC and AIR-1 co-depletion, and upon depletion of other known microtubule regulators, including TPXL-1/TPX2, ZYG-9/ch-TOG, PTRN-1/CAMSAP, and NOCA-1/Ninein. However, loss of GIP-1 removed a subset of dynamic EBP-2/EB1–marked microtubules, and the remaining dynamic microtubules grew faster. Together, these results suggest that different microtubule organizing centers (MTOCs) use discrete proteins for their function, and that the apical ncMTOC is composed of distinct populations of γ-TuRC-dependent and -independent microtubules that compete for a limited pool of resources.
Категории: Biology, Journals