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Andrew T Moehlman, Amanda K Casey, Kelly Servage, Kim Orth, Helmut Krämer
In response to environmental, developmental, and pathological stressors, cells engage homeostatic pathways to maintain their function. Among these pathways, the Unfolded Protein Response protects cells from the accumulation of misfolded proteins in the ER. Depending on ER stress levels, the ER-resident Fic protein catalyzes AMPylation or de-AMPylation of BiP, the major ER chaperone and regulator of the Unfolded Protein Response. This work elucidates the importance of the reversible AMPylation of BiP in maintaining the Drosophila visual system in response to stress...
July 17, 2018: ELife
David Jon Wasilko, Qingqiu Huang, Yuxin Mao
The causative agent of Legionnaires' disease, Legionella pneumophila , delivers more than 330 virulent effectors to its host to establish an intracellular membrane-bound organelle called the Legionella containing vacuole. Among the army of Legionella effectors, SidC and its paralog SdcA have been identified as novel bacterial ubiquitin (Ub) E3 ligases. To gain insight into the molecular mechanism of SidC/SdcA as Ub ligases, we determined the crystal structures of a binary complex of the N-terminal catalytic SNL domain of SdcA with its cognate E2 UbcH5C and a ternary complex consisting of the SNL domain of SidC with the Ub-linked E2 UbcH7...
July 17, 2018: ELife
Yara E Sanchez-Corrales, Guy B Blanchard, Katja Röper
The budding of tubular organs from flat epithelial sheets is a vital morphogenetic process. Cell behaviours that drive such processes are only starting to be unraveled. Using live-imaging and novel morphometric methods we show that in addition to apical constriction, radially-oriented directional intercalation of cells plays a major contribution to early stages of invagination of the salivary gland tube in the Drosophila embryo. Extending analyses in 3D, we find that near the pit of invagination, isotropic apical constriction leads to strong cell-wedging...
July 17, 2018: ELife
Junya Kato, Supratim Dey, Jose E Soto, Carmen Butan, Mason C Wilkinson, Roberto N De Guzman, Jorge E Galan
Type III protein secretion systems (T3SS) are encoded by several pathogenic or symbiotic bacteria. The central component of this nanomachine is the needle complex. Here we show in a Salmonella Typhimurium T3SS that assembly of the needle filament of this structure requires OrgC, a protein encoded within the T3SS gene cluster. Absence of OrgC results in significantly reduced number of needle substructures but does not affect needle length. We show that OrgC is secreted by the T3SS and that exogenous addition of OrgC can complement a ∆orgC mutation...
July 17, 2018: ELife
Lina Yao, Sarah Craven Seaton, Sula Ndousse-Fetter, Arijit A Adhikari, Nicholas DiBenedetto, Amir I Mina, Alexander S Banks, Lynn Bry, A Sloan Devlin
The human gut microbiota impacts host metabolism and has been implicated in the pathophysiology of obesity and metabolic syndromes. However, defining the roles of specific microbial activities and metabolites on host phenotypes has proven challenging due to the complexity of the microbiome-host ecosystem. Here, we identify strains from the abundant gut bacterial phylum Bacteroidetes that display selective bile salt hydrolase (BSH) activity. Using isogenic strains of wild-type and BSH-deleted Bacteroides thetaiotaomicron , we selectively modulated the levels of the bile acid tauro-b-muricholic acid in monocolonized gnotobiotic mice...
July 17, 2018: ELife
Frank Wolfgang Albert, Joshua S Bloom, Jake Siegel, Laura Day, Leonid Kruglyak
Heritable variation in gene expression forms a crucial bridge between genomic variation and the biology of many traits. However, most expression quantitative trait loci (eQTLs) remain unidentified. We mapped eQTLs by transcriptome sequencing in 1,012 yeast segregants. The resulting eQTLs accounted for over 70% of the heritability of mRNA levels, allowing comprehensive dissection of regulatory variation. Most genes had multiple eQTLs. Most expression variation arose from trans -acting eQTLs distant from their target genes...
July 17, 2018: ELife
Johan E Larsson, H Peter Larsson, Sara I Liin
The voltage-gated potassium channel KV 7.1 and the auxiliary subunit KCNE1 together form the cardiac IKs channel, which is a proposed target for future anti-arrhythmic drugs. We previously showed that polyunsaturated fatty acids (PUFAs) activate KV 7.1 via an electrostatic mechanism. The activating effect was abolished when KV 7.1 was co-expressed with KCNE1, as KCNE1 renders PUFAs ineffective by promoting PUFA protonation. PUFA protonation reduces the potential of PUFAs as anti-arrhythmic compounds. It is unknown how KCNE1 promotes PUFA protonation...
July 17, 2018: ELife
Christoph Brütting, Cristina Maria Crava, Martin Schäfer, Meredith C Schuman, Stefan Meldau, Nora Adam, Ian T Baldwin
Endophytic insects provide the textbook examples of herbivores that manipulate their host plant's physiology, putatively altering source/sink relationships by transferring cytokinins (CK) to create 'green islands' that increase the nutritional value of infested tissues. However, unambiguous demonstrations of CK transfer are lacking. Here we show that feeding by the free-living herbivore Tupiocoris notatus on Nicotiana attenuata is characterized by stable nutrient levels, increased CK levels and alterations in CK-related transcript levels in attacked leaves, in striking similarity to endophytic insects...
July 17, 2018: ELife
Yingsong Hao, Wenxing Yang, Jing Ren, Qi Hall, Yun Zhang, Joshua M Kaplan
Nitric oxide (NO) is released into the air by NO-producing organisms; however, it is unclear if animals utilize NO as a sensory cue. We show that C. elegans avoids Pseudomonas aeruginosa (PA14) in part by detecting PA14-produced NO. PA14 mutants deficient for NO production fail to elicit avoidance and NO donors repel worms. PA14 and NO avoidance are mediated by a chemosensory neuron (ASJ) and these responses require receptor guanylate cyclases and cyclic nucleotide gated ion channels. ASJ exhibits calcium increases at both the onset and removal of NO...
July 17, 2018: ELife
Andrew J Aman, Alexis N Fulbright, David M Parichy
Understanding how patterning influences cell behaviors to generate three dimensional morphologies is a central goal of developmental biology. Additionally, comparing these regulatory mechanisms among morphologically diverse tissues allows for rigorous testing of evolutionary hypotheses. Zebrafish skin is endowed with a coat of precisely patterned bony scales. We use in-toto live imaging during scale development and manipulations of cell signaling activity to elucidate core features of scale patterning and morphogenesis...
July 17, 2018: ELife
Evelyn Schubert, Ingrid R Vetter, Daniel Prumbaum, Pawel A Penczek, Stefan Raunser
α-Xenorhabdolysins (Xax) are α-pore-forming toxins (α-PFT) that form 1-1.3 MDa large pore complexes to perforate the host cell membrane. PFTs are used by a variety of bacterial pathogens to attack host cells. Due to the lack of structural information, the molecular mechanism of action of Xax toxins is poorly understood. Here, we report the cryo-EM structure of the XaxAB pore complex from Xenorhabdus nematophila and the crystal structures of the soluble monomers of XaxA and XaxB. The structures reveal that XaxA and XaxB are built similarly and appear as heterodimers in the 12-15 subunits containing pore, classifying XaxAB as bi-component α-PFT...
July 16, 2018: ELife
Corinne L Pender, H Robert Horvitz
The HIF (hypoxia-inducible factor) transcription factor is the master regulator of the metazoan response to chronic hypoxia. In addition to promoting adaptations to low oxygen, HIF drives cytoprotective mechanisms in response to stresses and modulates neural circuit function. How most HIF targets act in the control of the diverse aspects of HIF-regulated biology remains unknown. We discovered that a HIF target, the C. elegans gene cyp-36A1 , is required for numerous HIF-dependent processes, including modulation of gene expression, stress resistance, and behavior...
July 16, 2018: ELife
Skylar Xantus Kim, Gamze Çamdere, Xuchen Hu, Douglas Koshland, Hugo Tapia
Anhydrobiotes are rare microbes, plants and animals that tolerate severe water loss. Understanding the molecular basis for their desiccation tolerance may provide novel insights into stress biology and critical tools for engineering drought-tolerant crops. Using the anhydrobiote, budding yeast, we show that trehalose and Hsp12, a small intrinsically disordered protein (sIDP) of the hydrophilin family, synergize to mitigate completely the inviability caused by the lethal stresses of desiccation. We show that these two molecules help to stabilize the activity and prevent aggregation of model proteins both in vivo and in vitro ...
July 16, 2018: ELife
Saumel Ahmadi, Sunny Xia, Yu-Sheng Wu, Michelle Di Paola, Randolph Kissoon, Catherine Luk, Fan Lin, Kai Du, Johanna Rommens, Christine Bear
The severity of intestinal disease associated with Cystic Fibrosis (CF) is variable in the patient population and this variability is partially conferred by the influence of modifier genes. Genome-wide association studies have identified SLC6A14 , an electrogenic amino acid transporter, as a genetic modifier of CF-associated meconium ileus. The purpose of the current work was to determine the biological role of Slc6a14 , by disrupting its expression in CF mice bearing the major mutation, F508del. We found that disruption of Slc6a14 worsened the intestinal fluid secretion defect characteristic of these mice...
July 13, 2018: ELife
Xinyun Cao, Tobias Koch, Lydia Steffens, Julia Finkensieper, Renate Zigann, John E Cronan, Christiane Dahl
Many Bacteria and Archaea employ the heterodisulfide reductase (Hdr)-like sulfur oxidation pathway. The relevant genes are inevitably associated with genes encoding lipoate-binding proteins (LbpA). Here, deletion of the gene identified LbpA as an essential component of the Hdr-like sulfur-oxidizing system in the Alphaproteobacterium Hyphomicrobium denitrificans . Thus, a biological function was established for the universally conserved cofactor lipoate that is markedly different from its canonical roles in central metabolism...
July 13, 2018: ELife
Raymond E Hulse, Zongli Li, Rick K Huang, Jin Zhang, David E Clapham
We report the near atomic resolution (3.3 Å) of the human polycystic kidney disease 2-like 1 (polycystin 2-l1) ion channel. Encoded by PKD2L1, polycystin 2-l1 is a calcium and monovalent cation-permeant ion channel in primary cilia and plasma membranes. The related primary cilium-specific polycystin-2 protein, encoded by PKD2, shares a high degree of sequence similarity, yet has distinct permeability characteristics. Here we show that these differences are reflected in the architecture of polycystin 2-l1.
July 13, 2018: ELife
Erin G Conlon, Delphine Fagegaltier, Phaedra Agius, Julia Davis-Porada, James Gregory, Isabel Hubbard, Kristy Kang, Duyang Kim, Hemali Phatnani, Neil A Shneider, James L Manley
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of a disease spectrum with shared clinical, genetic and pathological features. These include near ubiquitous pathological inclusions of the RNA binding protein (RBP) TDP-43, and often the presence of a GGGGCC expansion in the C9ORF72 (C9) gene. Previously we reported that the sequestration of hnRNP H altered the splicing of target transcripts in C9ALS patients (Conlon et al. 2016). Here we show that this signature also occurs in half of 50 post-mortem sporadic, non-C9 ALS/FTD brains...
July 13, 2018: ELife
Omer Shafraz, Matthias Rübsam, Sara N Stahley, Amber Caldara, Andrew P Kowalczyk, Carien M Niessen, Sanjeevi Sivasankar
Desmosomes are adhesive junctions composed of two desmosomal cadherins: desmocollin (Dsc) and desmoglein (Dsg). Previous studies demonstrate that E-cadherin (Ecad), an adhesive protein that interacts in both trans and cis conformations, facilitates desmosome assembly via an unknown mechanism. Here we use structure-function analysis to resolve the mechanistic roles of Ecad in desmosome formation. Using AFM force measurements, we demonstrate that Ecad interacts with isoform 2 of Dsg via a conserved Leu-175 on the Ecad cis binding interface...
July 12, 2018: ELife
Luke H Chao, Jaebong Jang, Adam Johnson, Anthony Nguyen, Nathanael Gray, Priscilla L Yang, Stephen C Harrison
Dengue virus (DV) is a compact, icosahedrally symmetric, enveloped particle, covered by 90 dimers of envelope protein (E), which mediates viral attachment and membrane fusion. Fusion requires a dimer-to-trimer transition and membrane engagement of hydrophobic 'fusion loops'. We previously characterized the steps in membrane fusion for the related West Nile virus (WNV), using recombinant, WNV virus-like particles (VLPs) for single-particle experiments (Chao et al., 2014). Trimerization and membrane engagement are rate-limiting; fusion requires at least two adjacent trimers; availability of competent monomers within the contact zone between virus and target membrane creates a trimerization bottleneck...
July 12, 2018: ELife
Achim Werner, Regina Baur, Nia Teerikorpi, Deniz U Kaya, Michael Rape
Metazoan development depends on tightly regulated gene expression programs that instruct progenitor cells to adopt specialized fates. Recent work found that posttranslational modifications, such as monoubiquitylation, can determine cell fate also independently of effects on transcription, yet how monoubiquitylation is implemented during development is poorly understood. Here, we have identified a regulatory circuit that controls monoubiquitylation-dependent neural crest specification by the E3 ligase CUL3 and its substrate adaptor KBTBD8...
July 12, 2018: ELife
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