Person: Trauger, Sunia
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Trauger
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Sunia
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Trauger, Sunia
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Publication The anticancer natural product ophiobolin A induces cytotoxicity by covalent modification of phosphatidylethanolamine(eLife Sciences Publications, Ltd, 2016) Chidley, Christopher; Trauger, Sunia; Birsoy, Kıvanç; O'Shea, ErinPhenotypic screens allow the identification of small molecules with promising anticancer activity, but the difficulty in characterizing the mechanism of action of these compounds in human cells often undermines their value as drug leads. Here, we used a loss-of-function genetic screen in human haploid KBM7 cells to discover the mechanism of action of the anticancer natural product ophiobolin A (OPA). We found that genetic inactivation of de novo synthesis of phosphatidylethanolamine (PE) mitigates OPA cytotoxicity by reducing cellular PE levels. OPA reacts with the ethanolamine head group of PE in human cells to form pyrrole-containing covalent cytotoxic adducts and these adducts lead to lipid bilayer destabilization. Our characterization of this unusual cytotoxicity mechanism, made possible by unbiased genetic screening in human cells, suggests that the selective antitumor activity displayed by OPA may be due to altered membrane PE levels in cancer cells. DOI: http://dx.doi.org/10.7554/eLife.14601.001Publication The Metabolite α-Ketoglutarate Extends Lifespan by Inhibiting ATP Synthase and TOR(Nature Publishing Group, 2014) Chin, Randall M.; Fu, Xudong; Pai, Melody Y.; Vergnes, Laurent; Hwang, Heejun; Deng, Gang; Diep, Simon; Lomenick, Brett; Meli, Vijaykumar S.; Monsalve, Gabriela C.; Hu, Eileen; Whelan, Stephen A.; Wang, Jennifer; Jung, Gwanghyun; Solis, Gregory M.; Fazlollahi, Farbod; Kaweeteerawat, Chitrada; Quach, Austin; Nili, Mahta; Krall, Abby S.; Godwin, Hilary A.; Chang, Helena R.; Faull, Kym F.; Guo, Feng; Jiang, Meisheng; Trauger, Sunia; Saghatelian, Alan; Braas, Daniel; Christofk, Heather R.; Clarke, Catherine F.; Teitell, Michael A.; Petrascheck, Michael; Reue, Karen; Jung, Michael E.; Frand, Alison R.; Huang, JingMetabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms1, 2. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits3, 4. Recently, several metabolites have been identified that modulate ageing5, 6; however, the molecular mechanisms underlying this are largely undefined. Here we show that α-ketoglutarate (α-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit β is identified as a novel binding protein of α-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS)7. The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution8, 9. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan10, 11, 12, 13. We show that α-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by α-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by α-KG requires ATP synthase subunit β and is dependent on target of rapamycin (TOR) downstream. Endogenous α-KG levels are increased on starvation and α-KG does not extend the lifespan of dietary-restricted animals, indicating that α-KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.Publication Planarian regeneration in space: Persistent anatomical, behavioral, and bacteriological changes induced by space travel(John Wiley and Sons Inc., 2017) Morokuma, Junji; Durant, Fallon; Williams, Katherine B.; Finkelstein, Joshua M.; Blackiston, Douglas J.; Clements, Twyman; Reed, David W.; Roberts, Michael; Jain, Mahendra; Kimel, Kris; Trauger, Sunia; Wolfe, Benjamin E.; Levin, MichaelAbstract Regeneration is regulated not only by chemical signals but also by physical processes, such as bioelectric gradients. How these may change in the absence of the normal gravitational and geomagnetic fields is largely unknown. Planarian flatworms were moved to the International Space Station for 5 weeks, immediately after removing their heads and tails. A control group in spring water remained on Earth. No manipulation of the planaria occurred while they were in orbit, and space‐exposed worms were returned to our laboratory for analysis. One animal out of 15 regenerated into a double‐headed phenotype—normally an extremely rare event. Remarkably, amputating this double‐headed worm again, in plain water, resulted again in the double‐headed phenotype. Moreover, even when tested 20 months after return to Earth, the space‐exposed worms displayed significant quantitative differences in behavior and microbiome composition. These observations may have implications for human and animal space travelers, but could also elucidate how microgravity and hypomagnetic environments could be used to trigger desired morphological, neurological, physiological, and bacteriomic changes for various regenerative and bioengineering applications.Publication Transient protein-protein interactions perturb E. coli metabolome and cause gene dosage toxicity(eLife Sciences Publications, Ltd, 2016) Bhattacharyya, Sanchari; Bershtein, Shimon; Yan, Jin; Argun, Tijda; Gilson, Amy Ilana; Trauger, Sunia; Shakhnovich, EugeneGene dosage toxicity (GDT) is an important factor that determines optimal levels of protein abundances, yet its molecular underpinnings remain unknown. Here, we demonstrate that overexpression of DHFR in E. coli causes a toxic metabolic imbalance triggered by interactions with several functionally related enzymes. Though deleterious in the overexpression regime, surprisingly, these interactions are beneficial at physiological concentrations, implying their functional significance in vivo. Moreover, we found that overexpression of orthologous DHFR proteins had minimal effect on all levels of cellular organization – molecular, systems, and phenotypic, in sharp contrast to E. coli DHFR. Dramatic difference of GDT between ‘E. coli’s self’ and ‘foreign’ proteins suggests the crucial role of evolutionary selection in shaping protein-protein interaction (PPI) networks at the whole proteome level. This study shows how protein overexpression perturbs a dynamic metabolon of weak yet potentially functional PPI, with consequences for the metabolic state of cells and their fitness. DOI: http://dx.doi.org/10.7554/eLife.20309.001Publication The GPR 55 agonist, L-α-lysophosphatidylinositol, mediates ovarian carcinoma cell-induced angiogenesis(John Wiley & Sons, Ltd, 2015) Hofmann, Nicole A; Yang, Jiang; Trauger, Sunia; Nakayama, Hironao; Huang, Lan; Strunk, Dirk; Moses, Marsha; Klagsbrun, Michael; Bischoff, Joyce; Graier, Wolfgang FBackground and Purpose Highly vascularized ovarian carcinoma secretes the putative endocannabinoid and GPR55 agonist, L-α-lysophosphatidylinositol (LPI), into the circulation. We aimed to assess the involvement of this agonist and its receptor in ovarian cancer angiogenesis. Experimental Approach Secretion of LPI by three ovarian cancer cell lines (OVCAR-3, OVCAR-5 and COV-362) was tested by mass spectrometry. Involvement of cancer cell-derived LPI on angiogenesis was tested in the in vivo chicken chorioallantoic membrane (CAM) assay along with the assessment of the effect of LPI on proliferation, network formation, and migration of neonatal and adult human endothelial colony-forming cells (ECFCs). Engagement of GPR55 was verified by using its pharmacological inhibitor CID16020046 and diminution of GPR55 expression by four different target-specific siRNAs. To study underlying signal transduction, Western blot analysis was performed. Key Results Ovarian carcinoma cell-derived LPI stimulated angiogenesis in the CAM assay. Applied LPI stimulated proliferation, network formation, and migration of neonatal ECFCs in vitro and angiogenesis in the in vivo CAM. The pharmacological GPR55 inhibitor CID16020046 inhibited LPI-stimulated ECFC proliferation, network formation and migration in vitro as well as ovarian carcinoma cell- and LPI-induced angiogenesis in vivo. Four target-specific siRNAs against GPR55 prevented these effects of LPI on angiogenesis. These pro-angiogenic effects of LPI were transduced by GPR55-dependent phosphorylation of ERK1/2 and p38 kinase. Conclusions and Implications We conclude that inhibiting the pro-angiogenic LPI/GPR55 pathway appears a promising target against angiogenesis in ovarian carcinoma.Publication Identification of Residues in the Lipopolysaccharide ABC Transporter That Coordinate ATPase Activity with Extractor Function(American Society for Microbiology, 2016) Simpson, Brent W.; Owens, Tristan; Orabella, Matthew J.; Davis, Rebecca M.; May, Janine Margaret; Trauger, Sunia; Kahne, Daniel; Ruiz, NatividadABSTRACT The surface of most Gram-negative bacteria is covered with lipopolysaccharide (LPS), creating a permeability barrier against toxic molecules, including many antimicrobials. To assemble LPS on their surface, Gram-negative bacteria must extract newly synthesized LPS from the inner membrane, transport it across the aqueous periplasm, and translocate it across the outer membrane. The LptA to -G proteins assemble into a transenvelope complex that transports LPS from the inner membrane to the cell surface. The Lpt system powers LPS transport from the inner membrane by using a poorly characterized ATP-binding cassette system composed of the ATPase LptB and the transmembrane domains LptFG. Here, we characterize a cluster of residues in the groove region of LptB that is important for controlling LPS transport. We also provide the first functional characterization of LptFG and identify their coupling helices that interact with the LptB groove. Substitutions at conserved residues in these coupling helices compromise both the assembly and function of the LptB2FG complex. Defects in LPS transport conferred by alterations in the LptFG coupling helices can be rescued by changing a residue in LptB that is adjacent to functionally important residues in the groove region. This suppression is achieved by increasing the ATPase activity of the LptB2FG complex. Taken together, these data identify a specific binding site in LptB for the coupling helices of LptFG that is responsible for coupling of ATP hydrolysis by LptB with LptFG function to achieve LPS extraction.Publication How the glycosyltransferase OGT catalyzes amide bond cleavage(2016) Janetzko, John; Trauger, Sunia; Lazarus, Michael B.; Walker, SuzanneThe essential human enzyme O-GlcNAc transferase (OGT), known for modulating the functions of nuclear and cytoplasmic proteins through Ser/Thr glycosylation, was unexpectedly implicated in the proteolytic maturation of the cell cycle regulator host cell factor-1 (HCF-1). Here we show that HCF-1 cleavage occurs via glycosylation of a glutamate side chain followed by on-enzyme formation of an internal pyroglutamate, which undergoes spontaneous backbone hydrolysis.Publication Microstructures amplify carotenoid plumage signals in colorful tanagers(Cold Spring Harbor Laboratory, 2019-10-10) McCoy, Dakota; Shultz, Allison J.; Vidoudez, Charles; van der Heide, Emma; Dall, Jacqueline E.; Trauger, Sunia; Haig, DavidRed, orange, and yellow carotenoid-colored plumages have been considered honest signals of condition. We comprehensively quantified carotenoid signals in the social, sexually-dimorphic tanager genus Ramphocelus using scanning electron microscopy (SEM), finite-difference time-domain (FDTD) optical modeling, liquid chromatography–mass spectrometry (LC-MS), and spectrophotometry. Despite males having significantly more saturated color patches, males and females within a species have equivalent amounts and types of carotenoids. Male, but not female, feathers have elaborate microstructures which amplify color appearance. Expanded barbs enhance color saturation (for the same amount of pigment) by increasing the transmission of optical power through the feather. Dihedral barbules (vertically-angled, strap-shaped barbules) reduce total reflectance to generate “super black” plumage, an optical illusion to enhance nearby color. Dihedral barbules paired with red carotenoid pigment produce “velvet red” plumage. Together, our results suggest that a widely cited index of honesty—carotenoid pigments—cannot fully explain male appearance. We propose that males are selected to evolve amplifiers of honest signals—in this case, microstructures that enhance appearance —that are not necessarily themselves linked to quality.