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Cell Chemical Biology

Landon J Edgar, Norihito Kawasaki, Corwin M Nycholat, James C Paulson
Macrophages (MØs) expressing the endocytic sialic acid-binding immunoglobulin-like lectin 1 (siglec-1, CD169, sialoadhesin) are known to be adept at antigen capture-primarily due to their strategic location within lymphatic tissues. Antigen concentrated in these cells can be harnessed to induce potent anti-tumor/anti-pathogen cytotoxic (CD8+ ) T cell responses. Here, we describe a chemical platform that exploits the CD169-mediated antigen capture pathway for biased priming of antigen-specific CD4+ or CD8+ T cells in vivo...
October 24, 2018: Cell Chemical Biology
Anja Fux, Vadim S Korotkov, Markus Schneider, Iris Antes, Stephan A Sieber
Detection of dynamic protein-protein interactions within complexes and networks remains a challenging task. Here, we show by the example of the proteolytic ClpXP complex the utility of combined chemical cross-linking and mass spectrometry (XL-MS) to map interactions within ClpP and ClpX as well as across the enigmatic ClpX hexamer-ClpP heptamer interface. A few hot-spot lysines located in signature loops in ClpX were shown to be in proximity to several structural regions of ClpP providing an initial draft of the ClpX-ClpP interaction...
October 23, 2018: Cell Chemical Biology
Stefanie König, Erik Romp, Verena Krauth, Michael Rühl, Maximilian Dörfer, Stefanie Liening, Bettina Hofmann, Ann-Kathrin Häfner, Dieter Steinhilber, Michael Karas, Ulrike Garscha, Dirk Hoffmeister, Oliver Werz
5-Lipoxygenase (5-LO) initiates the biosynthesis of pro-inflammatory leukotrienes from arachidonic acid, which requires the nuclear membrane-bound 5-LO-activating protein (FLAP) for substrate transfer. Here, we identified human 5-LO as a molecular target of melleolides from honey mushroom (Armillaria mellea). Melleolides inhibit 5-LO via an α,β-unsaturated aldehyde serving as Michael acceptor for surface cysteines at the substrate entrance that are revealed as molecular determinants for 5-LO activity. Experiments with 5-LO mutants, where select cysteines had been replaced by serine, indicated that the investigated melleolides suppress 5-LO product formation via two distinct modes of action: (1) by direct interference with 5-LO activity involving two or more of the cysteines 159, 300, 416, and 418, and (2) by preventing 5-LO/FLAP assemblies involving selectively Cys159 in 5-LO...
October 23, 2018: Cell Chemical Biology
Kevin Huynh, Christopher K Barlow, Kaushala S Jayawardana, Jacquelyn M Weir, Natalie A Mellett, Michelle Cinel, Dianna J Magliano, Jonathan E Shaw, Brian G Drew, Peter J Meikle
High-throughput targeted lipid profiling with liquid chromatography-mass spectrometry (LC-MS) has been used extensively to identify associations between plasma lipid species and disease states. Such methods, used to characterize larger clinical cohorts, often suffer from an inability to differentiate isomeric forms of glycerophospholipids that are typically reported as the sum fatty acid carbons and double bonds. Here we report a chromatography gradient coupled with a detailed characterization of the human plasma lipidome to provide improved resolution and identification of 636 lipid species, including previously unreported species, in a 15-min analysis...
October 22, 2018: Cell Chemical Biology
Neri Amara, Ian T Foe, Ouma Onguka, Megan Garland, Matthew Bogyo
Palmitoylation is a post-translational modification involving the thioesterification of cysteine residues with a 16-carbon-saturated fatty acid. Little is known about rates of depalmitoylation or the parameters that dictate these rates. Here we report a modular strategy to synthesize quenched fluorogenic substrates for the specific detection of depalmitoylase activity and for mapping the substrate specificity of individual depalmitoylases. We demonstrate that human depalmitoylases APT1 and APT2, and TgPPT1 from the parasite Toxoplasma gondii, have distinct specificities that depend on amino acid residues distal to the palmitoyl cysteine...
October 22, 2018: Cell Chemical Biology
Ilsa T Kirby, Ana Kojic, Moriah R Arnold, Ann-Gerd Thorsell, Tobias Karlberg, Anke Vermehren-Schmaedick, Raashi Sreenivasan, Carsten Schultz, Herwig Schüler, Michael S Cohen
Poly-ADP-ribose polymerases (PARPs1-16) play pivotal roles in diverse cellular processes. PARPs that catalyze poly-ADP-ribosylation (PARylation) are the best characterized PARP family members because of the availability of potent and selective inhibitors for these PARPs. There has been comparatively little success in developing selective small-molecule inhibitors of PARPs that catalyze mono-ADP-ribosylation (MARylation), limiting our understanding of the cellular role of MARylation. Here we describe the structure-guided design of inhibitors of PARPs that catalyze MARylation...
October 18, 2018: Cell Chemical Biology
Shuen-Shiuan Wang, Xuefeng Gao, Virginia Del Solar, Xinheng Yu, Aristotelis Antonopoulos, Alan E Friedman, Eryn K Matich, G Ekin Atilla-Gokcumen, Mehrab Nasirikenari, Joseph T Lau, Anne Dell, Stuart M Haslam, Roger A Laine, Khushi L Matta, Sriram Neelamegham
Metabolic decoys are synthetic analogs of naturally occurring biosynthetic acceptors. These compounds divert cellular biosynthetic pathways by acting as artificial substrates that usurp the activity of natural enzymes. While O-linked glycosides are common, they are only partially effective even at millimolar concentrations. In contrast, we report that N-acetylglucosamine (GlcNAc) incorporated into various thioglycosides robustly truncate cell surface N- and O-linked glycan biosynthesis at 10-100 μM concentrations...
October 12, 2018: Cell Chemical Biology
Jonathan D Mortison, Monica Schenone, Jacob A Myers, Ziyang Zhang, Linfeng Chen, Christie Ciarlo, Eamon Comer, S Kundhavai Natchiar, Steven A Carr, Bruno P Klaholz, Andrew G Myers
Apart from their antimicrobial properties, tetracyclines demonstrate clinically validated effects in the amelioration of pathological inflammation and human cancer. Delineation of the target(s) and mechanism(s) responsible for these effects, however, has remained elusive. Here, employing quantitative mass spectrometry-based proteomics, we identified human 80S ribosomes as targets of the tetracyclines Col-3 and doxycycline. We then developed in-cell click selective crosslinking with RNA sequence profiling (icCL-seq) to map binding sites for these tetracyclines on key human rRNA substructures at nucleotide resolution...
October 5, 2018: Cell Chemical Biology
Emily S C Rittershaus, Seung-Hun Baek, Inna V Krieger, Samantha J Nelson, Yu-Shan Cheng, Subhalaxmi Nambi, Richard E Baker, John D Leszyk, Scott A Shaffer, James C Sacchettini, Christopher M Sassetti
Upon inhibition of respiration, which occurs in hypoxic or nitric oxide-containing host microenvironments, Mycobacterium tuberculosis (Mtb) adopts a non-replicating "quiescent" state and becomes relatively unresponsive to antibiotic treatment. We used comprehensive mutant fitness analysis to identify regulatory and metabolic pathways that are essential for the survival of quiescent Mtb. This genetic study identified a protein acetyltransferase (Mt-Pat/Rv0998) that promoted survival and altered the flux of carbon from oxidative to reductive tricarboxylic acid (TCA) reactions...
October 4, 2018: Cell Chemical Biology
Eddy T H Goh, Zhi Lin, Bo Young Ahn, Vanessa Lopes-Rodrigues, Ngoc Ha Dang, Shuhailah Salim, Bryan Berger, Brian Dymock, Donna L Senger, Carlos F Ibáñez
Small molecules offer powerful ways to alter protein function. However, most proteins in the human proteome lack small-molecule probes, including the large class of non-catalytic transmembrane receptors, such as death receptors. We hypothesized that small molecules targeting the interfaces between transmembrane domains (TMDs) in receptor complexes may induce conformational changes that alter receptor function. Applying this concept in a screening assay, we identified a compound targeting the TMD of death receptor p75NTR that induced profound conformational changes and receptor activity...
October 1, 2018: Cell Chemical Biology
Bryon S Drown, Tomohiro Shirai, Johannes Gregor Matthias Rack, Ivan Ahel, Paul J Hergenrother
The post-translational modification (PTM) and signaling molecule poly(ADP-ribose) (PAR) has an impact on diverse biological processes. This PTM is regulated by a series of ADP-ribosyl glycohydrolases (PARG enzymes) that cleave polymers and/or liberate monomers from their protein targets. Existing methods for monitoring these hydrolases rely on detection of the natural substrate, PAR, commonly achieved via radioisotopic labeling. Here we disclose a general substrate for monitoring PARG activity, TFMU-ADPr, which directly reports on total PAR hydrolase activity via release of a fluorophore; this substrate has excellent reactivity, generality (processed by the major PARG enzymes), stability, and usability...
September 28, 2018: Cell Chemical Biology
Shinsuke Araki, Yusuke Nakayama, Osamu Sano, Shoichi Nakao, Mari Shimizu-Ogasawara, Hiroyoshi Toyoshiba, Atsushi Nakanishi, Samuel Aparicio
Alternative polyadenylation (APA) plays a critical role in regulating gene expression. However, the balance between genome-encoded APA processing and autoregulation by APA modulating RNA binding protein (RBP) factors is not well understood. We discovered two potent small-molecule modulators of APA (T4 and T5) that promote distal-to-proximal (DtoP) APA usage in multiple transcripts. Monotonically responsive APA events, induced by short exposure to T4 or T5, were defined in the transcriptome, allowing clear isolation of the genomic sequence features and RBP motifs associated with DtoP regulation...
September 26, 2018: Cell Chemical Biology
Sana Sarvi, Richard Crispin, Yuting Lu, Lifan Zeng, Thomas D Hurley, Douglas R Houston, Alex von Kriegsheim, Che-Hong Chen, Daria Mochly-Rosen, Marco Ranzani, Marie E Mathers, Xiaowei Xu, Wei Xu, David J Adams, Neil O Carragher, Mayumi Fujita, Lynn Schuchter, Asier Unciti-Broceta, Valerie G Brunton, E Elizabeth Patton
5-Nitrofurans are antibiotic pro-drugs that have potential as cancer therapeutics. Here, we show that 5-nitrofurans can be bio-activated by aldehyde dehydrogenase (ALDH) 1A1/1A3 enzymes that are highly expressed in a subpopulation of cancer-initiating (stem) cells. We discover that the 5-nitrofuran, nifuroxazide, is selective for bio-activation by ALDH1 isoforms over ALDH2, whereby it both oxidizes ALDH1 and is converted to cytotoxic metabolites in a two-hit pro-drug mechanism. We show that ALDH1High melanoma cells are sensitive to nifuroxazide, while ALDH1A3 loss-of-function mutations confer drug resistance...
September 25, 2018: Cell Chemical Biology
Nina Grankvist, Jeramie D Watrous, Kim A Lagerborg, Yaroslav Lyutvinskiy, Mohit Jain, Roland Nilsson
Studying metabolic activities in living cells is crucial for understanding human metabolism, but facile methods for profiling metabolic activities in an unbiased, hypothesis-free manner are still lacking. To address this need, we here introduce the deep-labeling method, which combines a custom 13 C medium with high-resolution mass spectrometry. A proof-of-principle study on human cancer cells demonstrates that deep labeling can identify hundreds of endogenous metabolites as well as active and inactive pathways...
September 24, 2018: Cell Chemical Biology
Martin Kurnik, Cagla Sahin, Camilla Bertel Andersen, Nikolai Lorenzen, Lise Giehm, Hossein Mohammad-Beigi, Christian Moestrup Jessen, Jan Skov Pedersen, Gunna Christiansen, Steen Vang Petersen, Roland Staal, Girija Krishnamurthy, Keith Pitts, Peter H Reinhart, Frans A A Mulder, Scot Mente, Warren D Hirst, Daniel E Otzen
α-Synuclein (αSN) aggregation is central to the etiology of Parkinson's disease (PD). Large-scale screening of compounds to identify aggregation inhibitors is challenged by stochastic αSN aggregation and difficulties in detecting early-stage oligomers (αSOs). We developed a high-throughput screening assay combining SDS-stimulated αSN aggregation with FRET to reproducibly detect initial stages in αSN aggregation. We screened 746,000 compounds, leading to 58 hits that markedly inhibit αSN aggregation and reduce αSOs' membrane permeabilization activity...
August 29, 2018: Cell Chemical Biology
Max Berman Ferretti, Jennifer Louise Barre, Katrin Karbstein
Consistent with its location on the ribosome, reporter assays demonstrate a role for Rps26 in recognition of the Kozak sequence. Consequently, Rps26-deficient ribosomes display preference for mRNAs encoding components of the high salt and high pH stress response pathways and accumulate in yeast exposed to high salt or pH. Here we use this information to reprogram the cellular response to high salt by introducing point mutations in the Kozak sequence of key regulators for the cell wall MAP-kinase, filamentation, or DNA repair pathways...
August 24, 2018: Cell Chemical Biology
Christine A Marian, Mateusz Stoszko, Lili Wang, Matthew W Leighty, Elisa de Crignis, Chad A Maschinot, Jovylyn Gatchalian, Benjamin C Carter, Basudev Chowdhury, Diana C Hargreaves, Jeremy R Duvall, Gerald R Crabtree, Tokameh Mahmoudi, Emily C Dykhuizen
The persistence of a pool of latently HIV-1-infected cells despite combination anti-retroviral therapy treatment is the major roadblock for a cure. The BAF (mammalian SWI/SNF) chromatin remodeling complex is involved in establishing and maintaining viral latency, making it an attractive drug target for HIV-1 latency reversal. Here we report a high-throughput screen for inhibitors of BAF-mediated transcription in cells and the subsequent identification of a 12-membered macrolactam. This compound binds ARID1A-specific BAF complexes, prevents nucleosomal positioning, and relieves transcriptional repression of HIV-1...
August 23, 2018: Cell Chemical Biology
Arne Fabritius, David Ng, Andreas Michael Kist, Mutlu Erdogan, Ruben Portugues, Oliver Griesbeck
Protein engineering involves generating and screening large numbers of variants for desired properties. While modern DNA technology has made it easy to create protein diversity on the DNA level, the selection and validation of candidate proteins from large libraries remains a challenge. We built a screening platform that integrates high-quality fluorescence-based image analysis and robotic picking of bacterial colonies. It allows tracking each individual colony in a large population and collecting quantitative information on library composition during the protein evolution process...
August 22, 2018: Cell Chemical Biology
Shahzada Khan, Shigemoto Fujii, Tetsuro Matsunaga, Akira Nishimura, Katsuhiko Ono, Tomoaki Ida, Khandaker Ahtesham Ahmed, Tatsuya Okamoto, Hiroyasu Tsutsuki, Tomohiro Sawa, Takaaki Akaike
Reactive persulfides such as cysteine persulfide and glutathione persulfide are produced by bacteria including Salmonella during sulfur metabolism. The biological significance of bacterial reactive persulfides in host-pathogen interactions still warrants investigation. We found that reactive persulfides produced by Salmonella Typhimurium LT2 regulate macrophage autophagy via metabolizing 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), an electrophilic product of reactive oxygen species and nitric oxide signaling...
August 22, 2018: Cell Chemical Biology
Lin Guo, Wu Yang, Qiang Huang, Jiali Qiang, Jonathan Ross Hart, Wenyuan Wang, Junhao Hu, Jidong Zhu, Nan Liu, Yaoyang Zhang
Selenoproteins, defined by the presence of selenocysteines (Sec), play important roles in a wide range of biological processes. All known selenoproteins are marked by the presence of Sec insertion sequence (SECIS) at their mRNA. The lack of an effective analytical method has hindered our ability to explore the selenoproteome and new selenoproteins beyond SECIS. Here, we develop a Sec-specific mass spectrometry-based technique, termed "SecMS," which allows the systematic profiling of selenoproteomes by selective alkylation of Sec...
August 22, 2018: Cell Chemical Biology
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