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Journal of Biological Chemistry

Callie A S Corsa, Gemma L Pearson, Aaron Renberg, Matthew M Askar, Tracy Vozheiko, Ormond A MacDougald, Scott A Soleimanpour
The E3 ubiquitin ligase parkin is a critical regulator of mitophagy and has been identified as a susceptibility gene for type 2 diabetes (T2D). However, its role in metabolically active tissues that precipitate T2D development is unknown. Specifically, pancreatic β cells and adipocytes both rely heavily on mitochondrial function in the regulation of optimal glycemic control to prevent T2D, but parkin's role in preserving quality control of β-cell or adipocyte mitochondria is unclear. Although parkin has been previously reported to control mitophagy, here we show that parkin surprisingly is dispensable for glucose homeostasis in both β cells and adipocytes during diet-induced insulin resistance in mice...
March 15, 2019: Journal of Biological Chemistry
Haneul Yoo, Catherine Triandafillou, D Allan Drummond
In cells, phase separation creates two distinct liquid phases from a single mixed liquid phase, like oil droplets separating from water. Considerable attention has focused on how the products of phase separation-the resulting droplets-might act as biological compartments, bioreactors, filters, and membraneless organelles. Here we expand this perspective, reviewing recent results showing how cells instead use the process of phase separation to sense intracellular and extracellular changes. We review case studies in phase-separation-based sensing and discuss key features, such as extraordinary sensitivity, which make the process of phase separation ideally suited to meet a range of sensory challenges cells encounter...
March 15, 2019: Journal of Biological Chemistry
Ali A Kermani, Rana Roy, Chai Gopalasingam, Klaudia I Kocurek, Trushar R Patel, Luke J Alderwick, Gurdyal S Besra, Klaus Fütterer
A growing body of evidence implicates the mycobacterial capsule - the outermost layer of the mycobacterial cell envelope - in modulation of the host immune response and virulence of mycobacteria. Mycobacteria synthesize the dominant capsule component, α(1→4)-linked glucan, via three interconnected, and potentially redundant metabolic pathways. Here, we report the crystal structure of the Mycobacterium smegmatis TreS-Pep2 complex, containing trehalose synthase (TreS) and maltokinase (Pep2), which convert trehalose to maltose-1-phosphate as part of the TreS-Pep2-GlgE pathway...
March 15, 2019: Journal of Biological Chemistry
Rajaiah Pergu, Sunayana Dagar, Harsh Kumar, Rajesh Kumar, Jayanta Bhattacharya, Sivaram V S Mylavarapu
Tunneling NanoTubes (TNTs) are membrane conduits that mediate long-distance intercellular crosstalk in several organisms and play vital roles during development, pathogenic transmission, and cancer metastasis. However, the molecular mechanisms of TNT formation and function remain poorly understood. The protein MSec (also known as TNFα-induced protein 2 [TNFAIP2] and B94) is essential for TNT formation in multiple cell types. Here, using affinity protein purification, mass spectrometric identification, and confocal immunofluorescence microscopy assays, we found that MSec interacts with the endoplasmic reticulum (ER) chaperone ERp29...
March 15, 2019: Journal of Biological Chemistry
Gleb A Bazilevsky, Hayley C Affronti, Xuepeng Wei, Sydney L Campbell, Kathryn E Wellen, Ronen Marmorstein
ATP-citrate lyase (ACLY) is the predominant source of nucleocytosolic acetyl-CoA, a fundamental building block of carbon metabolism in eukaryotes. ACLY is aberrantly regulated in many cancers, cardiovascular disease, and metabolic disorders. However, the molecular mechanisms determining ACLY activity and function are unclear. To this end, we investigated the role of the uncharacterized ACLY C-terminal citrate synthase homology domain (CSHD) in the mechanism of acetyl-CoA formation. Using recombinant and purified ACLY and a suite of biochemical and biophysical approaches, including analytical ultracentrifugation, dynamic light scattering, and thermal stability assays, we demonstrate that the C-terminus maintains ACLY tetramerization, a conserved and essential quaternary structure in vitro and likely also in vivo...
March 15, 2019: Journal of Biological Chemistry
Aurore Labourel, Arnaud Baslé, Jose Munoz-Munoz, Didier Ndeh, Simon Booth, Sergey A Nepogodiev, Robert A Field, Alan Cartmell
The metabolism of carbohydrate polymers drives microbial diversity in the human gut microbiome. The selection pressures in this environment have spurred the evolution of a complex reservoir of microbial genes encoding carbohydrate-active enzymes (CAZymes). Previously, we have shown that the human gut bacterium Bacteroides thetaiotaomicron ( Bt ) can depolymerize the most structurally complex glycan, the plant pectin rhamnogalacturonan II (RGII), commonly found in the human diet. Previous investigation of the RGIIdegrading apparatus in Bt identified BT0997 as a new CAZyme family, classified as glycoside hydrolase 138 (GH138)...
March 15, 2019: Journal of Biological Chemistry
Philipp Graab, Christoph Bock, Konstantin Weiss, Alexander Hirth, Nicole Koller, Markus Braner, Jennifer Jung, Frank Loehr, Robert Tampé, Christian Behrends, Rupert Abele
The human lysosomal polypeptide ABC transporter TAPL (ABC subfamily B member 9, ABCB9) transports 6-59 amino-acids-long polypeptides from the cytosol into lysosomes. The subcellular localization of TAPL depends solely on its N-terminal transmembrane domain TMD0, which lacks conventional targeting sequences. However, the intracellular route and the molecular mechanisms that control TAPL localization remain unclear. Here, we delineated the route of TAPL to lysosomes and investigated the determinants of single trafficking steps...
March 15, 2019: Journal of Biological Chemistry
Tommy F Tashjian, Claudia Danilowicz, Anne-Elizabeth Molza, Brian H Nguyen, Chantal Prévost, Mara Prentiss, Veronica G Godoy
The evolutionarily conserved Escherichia coli translesion DNA Polymerase IV (DinB) is one of three enzymes that can bypass potentially deadly DNA lesions on the template strand during DNA replication. Remarkably, however, DinB is the only known translesion DNA polymerase active in RecA-mediated strand exchange during error-prone double strand break repair. In this process, a ssDNA-RecA nucleoprotein filament invades homologous dsDNA, pairing the ssDNA with the complementary strand in the dsDNA. When exchange reaches the 3' end of the ssDNA, a DNA polymerase can add nucleotides onto the end, using one strand of dsDNA as a template and displacing the other...
March 14, 2019: Journal of Biological Chemistry
Natarajan V Bhanu, Simone Sidoli, Zuo-Fei Yuan, Rosalynn C Molden, Benjamin A Garcia
We present a system-level analysis of proteome, phosphoproteome and chromatin state of precursors of muscle cells (myoblasts) differentiating into specialized myotubes. Using stable isotope labeling (SILAC) and nano-liquid chromatography-tandem mass spectrometry (nLC-MS/MS), we found that phosphorylation motifs targeted by the kinases PKC, CDK and MAPK showed increased phosphorylation during myodifferentiation of LHCN-M2 human skeletal myoblast cell line. Drugs known to inhibit these kinases either promoted (PD0325901 and GW8510) or stalled (CHIR99021 and roscovitine) differentiation, resulting in myotube-and myoblast phenotypes, respectively...
March 14, 2019: Journal of Biological Chemistry
Arti B Dumbrepatil, Soumi Ghosh, Kelcie A Zegalia, Paige A Malec, J Damon Hoff, Robert T Kennedy, E Neil G Marsh
Virus-inhibitory protein, endoplasmic reticulum-associated, interferon-inducible (viperin) is a radical SAM enzyme that plays a multifaceted role in the cellular antiviral response. Viperin has recently been shown to catalyze the SAM-dependent formation of 3'-deoxy-3',4'-didehydro-CTP (ddhCTP), which inhibits some viral RNA polymerases. Viperin is also implicated in regulating Lys-63-linked polyubiquitination of interleukin-1 receptor-associated kinase-1 (IRAK1) by the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6) as part of the Toll-like receptor-7 and 9 (TLR7/9) innate immune signaling pathways...
March 14, 2019: Journal of Biological Chemistry
Sashi Kant, Gangarao Davuluri, Khaled A Alchirazi, Nicole Welch, Claire Heit, Avinash Kumar, Mahesha Gangadhariah, Adam Kim, Megan R McMullen, Belinda Willard, Donal S Luse, Laura E Nagy, Vasilis Vasiliou, Anna Maria Marini, David Weiner, Srinivasan Dasarathy
Ethanol causes dysregulated muscle protein homeostasis while simultaneously causing hepatocyte injury. Since hepatocytes are the primary site for physiological disposal of ammonia, a cytotoxic cellular metabolite generated during a number of metabolic processes, we determined if hyperammonemia aggravates ethanol-induced muscle loss. Differentiated murine C2C12 myotubes, skeletal muscle from pair-fed or ethanol-treated mice and human patients with alcoholic cirrhosis and healthy controls were used to quantify protein synthesis, mTORC1 signaling and autophagy makers...
March 14, 2019: Journal of Biological Chemistry
Andrea Braganza, Kelly Quesnelle, Janelle Bickta, Christopher Reyes, Yinna Wang, Morgan Jessup, Claudette St Croix, Julie Scott, Shivendra V Singh, Sruti Shiva
Myoglobin is a monomeric heme protein expressed ubiquitously in skeletal and cardiac muscle and is traditionally considered to function as an oxygen reservoir for mitochondria during hypoxia. It is now well established that low concentrations of myoglobin are aberrantly expressed in a significant proportion of breast cancer tumors. Despite being expressed only at low levels in these tumors, myoglobin is associated with attenuated tumor growth and a better prognosis in breast cancer patients, but the mechanism of this myoglobin-mediated protection against further cancer growth remains unclear...
March 14, 2019: Journal of Biological Chemistry
Heledd H Jarosz-Griffiths, Nicola J Corbett, Helen A Rowland, Kate Fisher, Alys C Jones, Jennifer Baron, Gareth J Howell, Sally A Cowley, Satyan Chintawar, M Zameel Cader, Katherine A B Kellett, Nigel M Hooper
The cellular prion protein (PrPC ) is a key neuronal receptor for amyloid-β oligomers (AβO), mediating their neurotoxicity, which contributes to the neurodegeneration in Alzheimer's disease (AD). Similarly to the amyloid precursor protein (APP), PrPC is proteolytically cleaved from the cell surface by a disintegrin and metalloprotease, ADAM10. We hypothesized that ADAM10-modulated PrPC shedding would alter the cellular binding and cytotoxicity of AβO. Here, we found that in human neuroblastoma cells, activation of ADAM10 with the muscarinic agonist carbachol promotes PrPC shedding and reduces the binding of AβO to the cell surface, which could be blocked with an ADAM10 inhibitor...
March 14, 2019: Journal of Biological Chemistry
Munirah S Abd Rahim, Yevhen K Cherniavskyi, D Peter Tieleman, Sonja A Dames
The Ser/Thr protein kinase ataxia telangiectasia mutated (ATM) plays an important role in the DNA damage response, signaling in response to redox signals, the control of metabolic processes, and mitochondrial homeostasis. ATM localizes to the nucleus and at the plasma membrane, mitochondria, peroxisomes, and other cytoplasmic vesicular structures. It has been shown that the C-terminal FATC domain of human ATM (hATMfatc) can interact with a range of membrane mimetics and may thereby act as a membrane-anchoring unit...
March 13, 2019: Journal of Biological Chemistry
Kaouther Ben Ouirane, Yves Boulard, Stéphane Bressanelli
RNA viruses synthesize new genomes in the infected host thanks to dedicated, virally-encoded RNA-dependent RNA polymerases (RdRps). As such, these enzymes are prime targets for antiviral therapy, as has recently been demonstrated for hepatitis C virus (HCV). However, peculiarities in the architecture and dynamics of RdRps raise fundamental questions about access to their active site during RNA polymerization. Here, we used molecular modelling and molecular dynamics simulations, starting from the available crystal structures of HCV NS5B in ternary complex with template-primer duplexes and nucleotides, to address the question of ribonucleotide entry into the active site of viral RdRp...
March 13, 2019: Journal of Biological Chemistry
Huatao Chen, Lei Gao, Dan Yang, Yaoyao Xiao, Manhui Zhang, Cuimei Li, Aihua Wang, Yaping Jin
ELOVL3 is a very long-chain fatty acid elongase, and its mRNA levels display diurnal rhythmic changes exclusively in adult male mouse livers. This cyclical expression of hepatic Elovl3 is potentially controlled by the circadian clock, related hormones, and transcriptional factors. It remains unknown, however, if the circadian clock, in conjunction with androgen signaling, functions in maintaining the rhythmic expression of Elovl3 in a sexually dimorphic manner. Under either Zeitgeber or circadian time, WT mouse livers exhibited a robust circadian rhythmicity in the expression of circadian clock genes and Elovl3...
March 12, 2019: Journal of Biological Chemistry
Yuanlong Wu, Yanlong Li, Yaoyao Li, Yizan Ma, Yunlong Zhao, Chaozhi Wang, Huabin Chi, Miao Chen, Yuanhao Ding, Xiaoping Guo, Ling Min, XianLong Zhang
Cotton (Gossypium spp.) is one of the most important economic crops and exhibits yield-improving heterosis in specific hybrid combinations. The genic male-sterility system is the main strategy used for producing heterosis in cotton. To better understand the mechanisms of male sterility in cotton, we carried out 2-dimensional electrophoresis (2-DE) and label-free quantitative proteomics analysis in the anthers of two near-isogenic lines, the male-sterile line 1355A and the male-fertile line 1355B. We identified 39 and 124 proteins that were significantly differentially expressed between these two lines in the anthers at the tetrad stage (stage 7) and uninucleate pollen stage (stage 8), respectively...
March 12, 2019: Journal of Biological Chemistry
Stefan Klinker, Sabine Stindt, Lothar Gremer, Johannes G Bode, Christoph G W Gertzen, Holger Gohlke, Oliver H Weiergräber, Silke Hoffmann, Dieter Willbold
The hepatitis C virus (HCV) nonstructural protein 5A (NS5A) plays a key role in viral replication and virion assembly, and regulation of the assembly process critically depends on phosphorylation of both serine and threonine residues in NS5A. We previously identified SRC proto-oncogene, non-receptor tyrosine kinase (c-Src) as an essential host component of the HCV replication complex consisting of NS5A, the RNA-dependent RNA polymerase NS5B, and c-Src. Pull-down assays revealed an interaction between NS5A and the Src-homology 2 (SH2) domain of c-Src; however, the precise binding mode remains undefined...
March 12, 2019: Journal of Biological Chemistry
Iqbal Ahmad, Sunan Li, Rongrong Li, Qingqing Chai, Lixin Zhang, Bin Wang, Changqing Yu, Yong-Hui Zheng
Serine incorporator 5 (SERINC5) is a recently identified restriction factor that blocks virus entry but is antagonized by three unrelated retroviral accessory proteins. The S2 protein from equine infectious anemia virus (EIAV) has been reported to reduce SERINC5 expression at steady-state levels likely via the endocytic pathway; however, the precise mechanism is still unclear. Here, we investigated how EIAV S2 protein down-regulates SERINC5 compared with down-regulation induced by Nef from HIV-1 and glycoMA proteins from murine leukemia virus (MLV)...
March 12, 2019: Journal of Biological Chemistry
Yonathan Sonntag, Patrizia Gena, Anna Maggio, Tania Singh, Isabella Artner, Michal K Oklinski, Urban Johanson, Per Kjellbom, John Dirk Nieland, Søren Nielsen, Giuseppe Calamita, Michael Rützler
The aquaglyceroporins are a subfamily of aquaporins that conduct both water and glycerol. Aquaporin-3 (AQP3) has an important physiological function in renal water reabsorption, and AQP3-mediated hydrogen peroxide (H2 O2 ) permeability can enhance cytokine signaling in several cell types. The related aquaglyceroporin AQP7 is required for dendritic cell chemokine responses and antigen uptake. Selective small-molecule inhibitors are desirable tools for investigating the biological and pathological roles of these and other AQP isoforms...
March 11, 2019: Journal of Biological Chemistry
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