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PNAS Plus Significance Statements

PNAS Plus Significance Statements

PNAS August 5, 2014 111 (31) 11236-11237; https://doi.org/10.1073/pnas.ss11131
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Harmonization of initial estimates of shale gas life cycle greenhouse gas emissions for electric power generation

Garvin A. Heath, Patrick O’Donoughue, Douglas J. Arent, and Morgan Bazilian

Previously published life cycle assessments (LCAs) of greenhouse gas emissions from the production and use of shale gas have come to widely varying conclusions about both the magnitude of emissions and its comparison with conventionally produced natural gas and coal for electricity generation. We harmonize estimates from this literature to establish more consistently derived and robust summary of the current state of knowledge (pp. E3167–E3176). Whereas median estimates for both gas types appear less than half that of coal, alternative assumptions may lead to emissions approaching best-performing coal units, with implications for climate change mitigation strategies.

Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes

Guillermina M. Goñi, Carolina Epifano, Jasminka Boskovic, Marta Camacho-Artacho, Jing Zhou, Agnieszka Bronowska, M. Teresa Martín, Michael J. Eck, Leonor Kremer, Frauke Gräter, Francesco Luigi Gervasio, Mirna Perez-Moreno, and Daniel Lietha

Nonreceptor tyrosine kinases are major players in cell signaling. Among them, focal adhesion kinase (FAK) is the key integrator of signals from growth factors and cell adhesion. In cancer, FAK is frequently overexpressed, and by promoting adhesion to the tumor stroma and ECM, FAK provides important signals for tumor invasion and metastasis. Although autoinhibitory mechanisms have previously been described and the players involved in FAK regulation are largely known, on a mechanistic level, FAK activation is currently not understood. Here (pp. E3177–E3186), we present a multidisciplinary approach demonstrating a multistep mechanism resulting in FAK activation. This mechanistic insight enables the design of alternative strategies for the discovery of potential anticancer drugs that inhibit both catalytic and scaffolding functions of FAK with high specificity.

Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G

Evangelos Papadopoulos, Simon Jenni, Eihab Kabha, Khuloud J. Takrouri, Tingfang Yi, Nicola Salvi, Rafael E. Luna, Evripidis Gavathiotis, Poornachandran Mahalingam, Haribabu Arthanari, Ricard Rodriguez-Mias, Revital Yefidoff-Freedman, Bertal H. Aktas, Michael Chorev, Jose A. Halperin, and Gerhard Wagner

eIF4E is critical for protein synthesis and becomes hyperactive in cancer cells. Small-molecule inhibitors of the eIF4E/eIF4G initiation factor complex have recently been found to exhibit antitumor activity in vitro and in vivo. However, their mode of action at the atomic level has remained elusive. Here (pp. E3187–E3195), we report high-resolution crystal structures of complexes of 4EGI-1 analogue inhibitors with eIF4E. We find that inhibition of eIF4G binding must be allosteric, because the 4EGI-1 and eIF4G bind at distant epitopes on eIF4E. Compound binding induces extension of an α-helix that stretches between the two binding sites. Indeed, mutations increasing helix propensity in this region reduce eIF4G affinity in the absence of the inhibitor, which is consistent with the proposed allosteric model.

Side-chain conformation at the selectivity filter shapes the permeation free-energy landscape of an ion channel

Tyler J. Harpole and Claudio Grosman

Our mutagenesis work on the ring of glutamates in the charge-selectivity filter region of the muscle nicotinic acetylcholine receptor led us to propose that the rate at which ions permeate through the open channel depends not only on the number of these glutamates, but also on the conformation of their side chains. Because our inferences were made on the basis of electrophysiological observations, however, we decided to test the plausibility of these ideas using computer simulations. Remarkably, the simulations (pp. E3196–E3205) gave ample credence to all aspects of our proposal and allowed us to gain insight into the effect of specific glutamate rotamers on single-channel conductance.

Type-I interferon signaling through ISGF3 complex is required for sustained Rip3 activation and necroptosis in macrophages

Scott McComb, Erin Cessford, Norah A. Alturki, Julie Joseph, Bojan Shutinoski, Justyna B. Startek, Ana M. Gamero, Karen L. Mossman, and Subash Sad

Although it has long been known that inflammatory immune responses are associated with death of cells through necrosis, the mechanisms controlling this process are not yet well understood. Recently a type of programmed inflammatory cell death, necroptosis, has been discovered. In this paper we reveal previously unidentified molecular mechanisms that operate to induce this form of cell death. Our results (pp. E3206–E3213) indicate that in order to undergo necroptosis, immune cells must produce and receive signals from the key immune regulator, interferon. Such interferon-dependent necroptosis of immune cells drives acute inflammatory pathology in a mouse model of sepsis. This work highlights the intimate connection between cell death and inflammation, and may lead to new understanding and treatment of inflammatory pathologies.

Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells

Pablo F. Céspedes, Susan M. Bueno, Bruno A. Ramírez, Roberto S. Gomez, Sebastián A. Riquelme, Christian E. Palavecino, Juan Pablo Mackern-Oberti, Jorge E. Mora, David Depoil, Catarina Sacristán, Michael Cammer, Alison Creneguy, Tuan H. Nguyen, Claudia A. Riedel, Michael L. Dustin, and Alexis M. Kalergis

Human respiratory syncytial virus (hRSV) is the leading cause of bronchiolitis and pneumonia in children worldwide. The induction of poor T-cell immunological memory causes a high susceptibility to reinfections, which contributes to hRSV spread. Previously, we showed that hRSV inhibits T-cell activation by impairing the assembly of the dendritic cell (DC)−T-cell immunological synapse (IS). Here (pp. E3214–E3223), we show that the nucleoprotein (N) of hRSV—a canonical cytosolic protein—is expressed on the surface of infected DCs. Further, using the supported-lipid-bilayer system (that mimics the DC/ antigen-presenting cells-membrane composition), we observed that the hRSV N interfered with pMHC−T-cell receptor interactions and inhibited IS assembly. We conclude that hRSV N may therefore be instrumental in impairing the host immune response during infection with this virus.

Toll-like receptor 9 signaling acts on multiple elements of the germinal center to enhance antibody responses

Derek C. Rookhuizen and Anthony L. DeFranco

The antibody response of B lymphocytes proceeds in two phases, a rapid low-affinity response and a slower germinal center (GC) response that is responsible for high-affinity antibody, long-lived antibody-secreting cells, and high-affinity memory B cells. We have examined (pp. E3224–E3233) how immune cell recognition of foreign nucleic acid by Toll-like receptors enhances the GC response and found that it does so by multiple complementary mechanisms. Recognition of foreign nucleic acid by dendritic cells led to increased numbers of helper T cells and GC B cells. In contrast, recognition by the antigen-specific B cells promoted the selection of high-affinity B cells and their differentiation into memory B cells, both of which are central goals for vaccination.

Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis

Ting Wang, Daniele M. Gilkes, Naoharu Takano, Lisha Xiang, Weibo Luo, Corey J. Bishop, Pallavi Chaturvedi, Jordan J. Green, and Gregg L. Semenza

Cancer cells release from their cell surface membrane-lined microvesicles (MVs), which contain proteins, mRNAs, and microRNAs that can be taken up by other cells. We report that breast cancer cells exposed to decreased oxygen availability (hypoxia) increase their production of MVs, which stimulate invasion and metastasis by recipient breast cancer cells. Increased MV shedding by hypoxic cells requires expression of hypoxia-inducible factors (HIFs), which activate transcription of the RAB22A gene, and expression of the small GTPase RAB22A, which is a protein that localizes to budding MVs. Our results (pp. E3234–E3242) delineate a molecular mechanism by which hypoxia increases invasion and metastasis by stimulating MV shedding and provide further evidence that addition of HIF inhibitors to current treatment regimens may improve clinical outcome.

Subpolar addition of new cell wall is directed by DivIVA in mycobacteria

Xavier Meniche, Renee Otten, M. Sloan Siegrist, Christina E. Baer, Kenan C. Murphy, Carolyn R. Bertozzi, and Christopher M. Sassetti

The tropomyosin-like protein, DivIVA, determines the site of growth and cell morphology in mycobacteria. Surprisingly, although DivIVA is located at the tip of the growing cell pole, cell wall addition is excluded from this site. Both late cell wall synthetic enzymes and new cell wall deposition occur at a subpolar space, distinct from the DivIVA-marked cell tip. Instead of directly recruiting terminal cell wall synthetic systems, DivIVA interacts with enzymes involved in the early steps of the cell wall precursor synthesis. These results (pp. E3243–E3251) suggest a unique organization of the polar elongasome, where cell wall precursors are concentrated at the cell tip by DivIVA and then incorporated into the nascent cell wall in an annular pattern at the subpolar zone.

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PNAS Plus Significance Statements
Proceedings of the National Academy of Sciences Aug 2014, 111 (31) 11236-11237; DOI: 10.1073/pnas.ss11131

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PNAS Plus Significance Statements
Proceedings of the National Academy of Sciences Aug 2014, 111 (31) 11236-11237; DOI: 10.1073/pnas.ss11131
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  • Article
    • Harmonization of initial estimates of shale gas life cycle greenhouse gas emissions for electric power generation
    • Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes
    • Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G
    • Side-chain conformation at the selectivity filter shapes the permeation free-energy landscape of an ion channel
    • Type-I interferon signaling through ISGF3 complex is required for sustained Rip3 activation and necroptosis in macrophages
    • Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells
    • Toll-like receptor 9 signaling acts on multiple elements of the germinal center to enhance antibody responses
    • Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis
    • Subpolar addition of new cell wall is directed by DivIVA in mycobacteria
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