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From Membrane to Nucleus: A Three-Wave Hypothesis of cAMP Signaling J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-26 Alejandro Pizzoni, Xuefeng Zhang, Daniel L. Altschuler
For many decades, our understanding of G protein-coupled receptor (GPCR) activity and cyclic AMP (cAMP) signaling was limited exclusively to the plasma membrane. However, a growing body of evidence has challenged this view by introducing the concept of endocytosis-dependent GPCR signaling. This emerging paradigm emphasizes not only the sustained production of cAMP but also its precise subcellular localization
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Protocatechuate hydroxylase is a novel group A flavoprotein monooxygenase with a unique substrate recognition mechanism J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-28 Nozomi Katsuki, Riku Fukushima, Yuki Doi, Shunsuke Masuo, Takatoshi Arakawa, Chihaya Yamada, Shinya Fushinobu, Naoki Takaya
Para-hydroxybenzoate hydroxylase (PHBH) is a group A flavoprotein monooxygenase that hydroxylates p-hydroxybenzoate to protocatechuate (PCA). Despite intensive studies of Pseudomonas aeruginosa p-hydroxybenzoate hydroxylase (PaPobA), the catalytic reactions of extremely diverse putative PHBH isozymes remain unresolved. We analyzed the phylogenetic relationships of known and predicted PHBHs and identified
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Characterization of the cystargolide biosynthetic gene cluster and functional analysis of the methyltransferase CysG J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-27 Patrick Beller, Phillipp Fink, Felix Wolf, Daniel Männle, Irina Helmle, Wolfgang Kuttenlochner, Daniel Unterfrauner, Alicia Engelbrecht, Nicole D. Staudt, Andreas Kulik, Michael Groll, Harald Gross, Leonard Kaysser
Cystargolides are natural products originally isolated from Kitasatospora cystarginea NRRL B16505 as inhibitors of the proteasome. They are composed of a dipeptide backbone linked to a β-lactone warhead. Recently, we identified the cystargolide biosynthetic gene cluster but systematic genetic analyses had not been carried out because of the lack of a heterologous expression system. Here, we report
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The dangerous liaisons in innate immunity involving recombinant proteins and endotoxins: examples from the literature and the Leptospira field J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-27 Delphine Bonhomme, Jean-Marc Cavaillon, Catherine Werts
Endotoxins, also known as lipopolysaccharides (LPS), are essential components of cell walls of diderm bacteria such as Escherichia coli (E. coli). LPS are microbe-associated molecular patterns (MAMPs) that can activate pattern recognition receptors (PRRs). While trying to investigate the interactions between proteins and host innate immunity, some studies using recombinant proteins expressed in E.
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When Argonaute takes out the ribonuclease sword J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-27 Kotaro Nakanishi
Argonaute (AGO) proteins in all three domains of life form ribonucleoprotein or deoxyribonucleoprotein complexes by loading a guide RNA or DNA, respectively. Since all AGOs retain a PIWI domain that takes an RNase H fold, the ancestor was likely an endoribonuclease (i.e., a slicer). In animals, most microRNA (miRNA)-mediated gene silencing occurs slicer-independently. However, the slicer activity of
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Fatty acids and inflammatory stimuli induce expression of long-chain acyl-CoA synthetase 1 to promote lipid remodeling in diabetic kidney disease J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-26 Chih-Hong Wang, S. Surbhi, Sayhaan Goraya, Jaeman Byun, Subramaniam Pennathur
Fatty acid handling and complex lipid synthesis are altered in the kidney cortex of diabetic patients. We recently showed that inhibition of the renin-angiotensin system without changes in glycemia can reverse diabetic kidney disease (DKD) and restore the lipid metabolic network in the kidney cortex of diabetic (db/db) mice, raising the possibility that lipid remodeling may play a central role in DKD
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The reversible inhibitor SR-4835 binds Cdk12/Cyclin K in a non-canonical G-loop conformation J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-26 Maximilian Schmitz, Ines H. Kaltheuner, Kanchan Anand, Robert Düster, Jonas Moecking, Andrii Monastyrskyi, Derek R. Duckett, William R. Roush, Matthias Geyer
Inhibition of cyclin-dependent kinases (CDKs) has evolved as an emerging anti-cancer strategy. In addition to the cell cycle-regulating CDKs, the transcriptional kinases Cdk12 and Cdk13 have become the focus of interest as they mediate a variety of functions, including the transition from transcription initiation to elongation and termination, precursor mRNA splicing, and intronic polyadenylation.
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The specificity landscape of bacterial ribonuclease P J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-25 Alexandra R. Chamberlain, Loc Huynh, Wei Huang, Derek J. Taylor, Michael E. Harris
Developing quantitative models of substrate specificity for RNA processing enzymes is a key step toward understanding their biology and guiding applications in biotechnology and biomedicine. Optimally, models to predict relative rate constants for alternative substrates should integrate an understanding of structures of the enzyme bound to ‘fast’ and ‘slow’ substrates, large datasets of rate constants
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Thermococcus kodakarensis TK0353 is a novel AP lyase with a new fold J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-25 Paul J. Caffrey, Brian E. Eckenroth, Brett W. Burkhart, Kelly M. Zatopek, Colleen M. McClung, Thomas J. Santangelo, Sylvie Doublié, Andrew F. Gardner
Hyperthermophilic organisms thrive in extreme environments prone to high levels of DNA damage. Growth at high temperature stimulates DNA base hydrolysis resulting in apurinic/apyrimidinic (AP) sites that destabilize the genome. Organisms across all domains have evolved enzymes to recognize and repair AP sites to maintain genome stability. The hyperthermophilic archaeon Thermococcus kodakarensis encodes
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Intracellular sphingolipid sorting drives membrane phase separation in the yeast vacuole J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-25 Hyesoo Kim, Itay Budin
The yeast vacuole membrane can phase separate into ordered and disordered domains, a phenomenon that is required for micro-lipophagy under nutrient limitation. Despite its importance as a biophysical model and physiological significance, it is not yet resolved if specific lipidome changes drive vacuole phase separation. Here we report that the metabolism of sphingolipids (SLs) and their sorting into
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Inhibition of the urea cycle by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin increases serum ammonia levels in mice J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-25 Giovan N. Cholico, Russell R. Fling, Warren J. Sink, Rance Nault, Tim Zacharewski
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor known for mediating the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. TCDD induces non-alcoholic fatty liver disease (NAFLD)-like pathologies including simple steatosis that can progress to steatohepatitis with fibrosis and bile duct proliferation in male mice. Dose-dependent progression of
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The multi-step oxidation of cholesterol to pregnenolone by human cytochrome P450 11A1 is highly processive J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-24 Kevin D. McCarty, Lu Liu, Yasuhiro Tateishi, Hannah L. Wapshott-Stehli, F. Peter Guengerich
Cytochrome P450 (P450, CYP) 11A1 is the classical cholesterol side chain cleavage enzyme (P450scc) that removes six carbons of the side chain, the first and rate-limiting step in the synthesis of all mammalian steroids. The reaction is a 3-step, 6-electron oxidation that proceeds via formation of 22R-hydroxy (OH) and 20R,22R-(OH)2 cholesterol, yielding pregnenolone. We expressed human P450 11A1 in
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Exosomal miR-23a-3p derived from human umbilical cord mesenchymal stem cells promotes remyelination in central nervous system demyelinating diseases by targeting Tbr1/Wnt pathway J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-22 Danqing Qin, Chunjuan Wang, Dong Li, Shougang Guo
Oligodendrocyte precursor cells (OPCs) are present in the adult central nervous system (CNS), and their impaired ability to differentiate into myelinating oligodendrocytes (OLs) can lead to demyelination in patients with multiple sclerosis (MS), accompanied by neurological deficits and cognitive impairment. Exosomes, small vesicles released by cells, are known to facilitate intercellular communication
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β-arrestin1 is an E3 ubiquitin ligase adaptor for substrate linear polyubiquitination J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-21 Chandler J. McElrath, Sara Benzow, Ya Zhuo, Adriano Marchese
G protein-coupled receptor (GPCR) signaling and trafficking are regulated by multiple mechanisms, including post-translational modifications such as ubiquitination by E3 ubiquitin ligases. E3 ligases have been linked to agonist-stimulated ubiquitination of GPCRs via simultaneous binding to βarrestins. In addition, βarrestins have been suggested to assist E3 ligases for ubiquitination of key effector
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Unusual 1-3 peptidoglycan cross-links in Acetobacteraceae are made by L,D-transpeptidases with a catalytic domain distantly related to YkuD domains J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-23 Marcel G. Alaman-Zarate, Brooks J. Rady, Caroline A. Evans, Brooke Pian, Darren Greetham, Sabrina Marecos-Ortiz, Mark J. Dickman, Ian DEA. Lidbury, Andrew L. Lovering, Buz M. Barstow, Stéphane Mesnage
Peptidoglycan is an essential component of the bacterial cell envelope that contains glycan chains substituted by short peptide stems. Peptide stems are polymerized by D,D-transpeptidases, which make bonds between the amino acid in position 4 of a donor stem and the third residue of an acceptor stem (4-3 cross-links). Some bacterial peptidoglycans also contain 3-3 cross-links that are formed by another
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Klebsiella pneumoniae carbapenemase variant 44 (KPC-44) acquires ceftazidime-avibactam resistance by altering the conformation of active site loops J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-23 Zhizeng Sun, Hanfeng Lin, Liya Hu, Neetu Neetu, Banumathi Sankaran, Jin Wang, B.V. Venkataram Prasad, Timothy Palzkill
Klebsiella pneumoniae carbapenemase 2 (KPC-2) is an important source of drug resistance as it can hydrolyze and inactivate virtually all β-lactam antibiotics. KPC-2 is potently inhibited by avibactam via formation of a reversible carbamyl linkage of the inhibitor with the catalytic serine of the enzyme. However, the use of avibactam in combination with ceftazidime (CAZ-AVI) has led to the emergence
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Combined inhibition of MTAP and MAT2a mimics synthetic lethality in tumor models via PRMT5 inhibition J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-23 Gabriel T. Bedard, Nord Gilaj, Karina Peregrina, Isabella Brew, Elena Tosti, Karl Shaffer, Peter C. Tyler, Winfried Edelmann, Leonard H. Augenlicht, Vern L. Schramm
Homozygous 5’-methylthioadenosine phosphorylase (MTAP) deletions occur in approximately 15% of human cancers. Co-deletion of MTAP and methionine adenosyltransferase 2 alpha (MAT2a) induces a synthetic lethal phenotype involving protein arginine methyltransferase 5 (PRMT5) inhibition. MAT2a inhibitors are now in clinical trials for genotypic MTAP-/- cancers, however the MTAP-/- genotype represents fewer
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A regulatory role for the unstructured C-terminal domain of the CtBP transcriptional corepressor J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-23 Ana-Maria Raicu, Megha Suresh, David N. Arnosti
The C-terminal Binding Protein (CtBP) is a transcriptional corepressor that plays critical roles in development, tumorigenesis, and cell fate. CtBP proteins are structurally similar to alpha hydroxyacid dehydrogenases and feature a prominent intrinsically disordered region in the C-terminus. In the mammalian system, CtBP proteins lacking the C-terminal Domain (CTD) are able to function as transcriptional
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Overexpression of AMPKγ2 increases AMPK signaling to augment human T cell metabolism and function J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-22 Erica L. Braverman, Margaret A. McQuaid, Herbert Schuler, Mengtao Qin, Sophia Hani, Keli Hippen, Darlene A. Monlish, Andrea K. Dobbs, Manda J. Ramsey, Felicia Kemp, Christopher Wittmann, Archana Ramgopal, Harrison Brown, Bruce Blazar, Craig A. Byersdorfer
Cellular therapies are currently employed to treat a variety of disease processes. For T cell-based therapies, success often relies on the metabolic fitness of the T cell product, where cells with enhanced metabolic capacity demonstrate improved in vivo efficacy. AMP-activated protein kinase (AMPK) is a cellular energy sensor which combines environmental signals with cellular energy status to enforce
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Complex II ambiguities ― FADH2 in the electron transfer system J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-22 Erich Gnaiger
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Structure and biochemical characterization of L-2-hydroxyglutarate dehydrogenase and its role in the pathogenesis of L-2-hydroxyglutaric aciduria J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-22 Jun Yang, Xingchen Chen, Shan Jin, Jianping Ding
L-2-hydroxyglutarate dehydrogenase (L2HGDH) is a mitochondrial membrane associated metabolic enzyme, which catalyzes the oxidation of L-2-hydroxyglutarate (L-2-HG) to 2-oxoglutarate (2-OG). Mutations in human L2HGDH lead to abnormal accumulation of L-2-HG which causes a neurometabolic disorder named L-2-hydroxyglutaric aciduria (L-2-HGA). Here, we report the crystal structures of Drosophila melanogaster
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Association of DDX5/p68 protein with the upstream erythroid enhancer element (EHS1) of the gene encoding the KLF1 transcription factor J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-22 Xiaoyong Chen, Sanjana Pillay, Felix Lohmann, James J. Bieker
EKLF/KLF1 is an essential transcription factor that plays a global role in erythroid transcriptional activation. Regulation of KLF1 is of interest, as it displays a highly restricted expression pattern, limited to erythroid cells and its progenitors. Here we use biochemical affinity purification to identify the DDX5/p68 protein as an activator of KLF1 by virtue of its interaction with the erythroid-specific
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Membrane lipid modulations by methyl-β-cyclodextrin uncouple the Drosophila light-activated phospholipase C from TRP and TRPL channel gating J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-21 Rita Gutorov, Ben Katz, Maximilian Peters, Baruch Minke
Sterols are hydrophobic molecules, known to cluster signaling membrane-proteins in lipid-rafts, while methyl-β-cyclodextrin (MβCD) has been a major tool for modulating membrane-sterol content to study its effect on membrane proteins, including the Transient Receptor Potential (TRP) channels. The Drosophila light-sensitive TRP channels are activated downstream of a G-protein-coupled phospholipase Cβ
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miR-125a-5p/miR-125b-5p contributes to pathological activation of Angiotensin II-AT1R in mouse distal convoluted tubule cells by the suppression of Atrap J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-21 Keigo Hirota, Akio Yamashita, Eriko Abe, Takahiro Yamaji, Kengo Azushima, Shohei Tanaka, Shinya Taguchi, Shunichiro Tsukamoto, Hiromichi Wakui, Kouichi Tamura
The renin-angiotensin system (RAS) plays a crucial role in the regulation of blood pressure. Activation of the angiotensin II (Ang II)-Ang II type 1 receptor (AT1R) signaling pathway contributes to the pathogenesis of hypertension and subsequent organ damage. AT1R-associated protein (ATRAP) has been identified as an endogenous inhibitory protein of the AT1R pathological activation. We have shown that
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A Surge of Cytosolic Calcium Dysregulates Lysosomal Function and Impairs Autophagy Flux during Cupric Chloride-Induced Neuronal Death J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-21 Yoonkyung Kim, Yangsin Lee, Minjung Choo, Nuri Yun, Jin Won Cho, Young J. Oh
Autophagy is a degradative pathway that plays an important role in maintaining cellular homeostasis. Dysfunction of autophagy is associated with the progression of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Although one of the typical features of brain aging is an accumulation of redox-active metals that eventually lead to neurodegeneration
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Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-21 Zsuzsa Radvanyi, Eun Jin Yoo, Palanivel Kandasamy, Adrian Salas-Bastos, Sophie Monnerat, Julie Refardt, Mirjam Christ-Crain, Himeka Hayashi, Yasuhiko Kondo, Jonathan Jantsch, Isabel Rubio-Aliaga, Lukas Sommer, Carsten A. Wagner, Matthias A. Hediger, Hyug Moo Kwon, Johannes Loffing, Ganesh Pathare
The bone-derived hormone fibroblast growth factor-23 (FGF23) has recently received much attention due to its association with chronic kidney disease and cardiovascular disease progression. Extracellular sodium concentration ([Na+]) plays a significant role in bone metabolism. Hyponatremia (lower serum [Na+]) has recently been shown to be independently associated with FGF23 levels in patients with chronic
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Testicular ACE regulates sperm metabolism and fertilization through the transcription factor PPARγ J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-20 Tomohiro Shibata, Shabir A. Bhat, DuoYao Cao, Suguru Saito, Ellen A. Bernstein, Erika Nishi, Juliet D. Medenilla, Erica T. Wang, Jessica L. Chan, Margareta D. Pisarska, Warren G. Tourtellotte, Jorge F. Giani, Kenneth E. Bernstein, Zakir Khan
Testis angiotensin-converting enzyme (tACE) plays a critical role in male fertility, but the mechanism is unknown. Sperm motility and fertilization depend on energy metabolism. By using ACE C-domain knockout (CKO) mice which lack tACE activity, we found that ATP in CKO sperm was 9.4-fold lower than WT sperm. Similarly, an ACE inhibitor (ACEi) reduced ATP production in mouse sperm by 72%. Metabolic
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A simple assay for inhibitors of mycobacterial oxidative phosphorylation J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-20 Serena A. Harden, Gautier M. Courbon, Yingke Liang, Angelina S. Kim, John L. Rubinstein
Oxidative phosphorylation, the combined activities of the electron transport chain (ETC) and adenosine triphosphate (ATP) synthase, has emerged as a valuable target for antibiotics to treat infection with Mycobacterium tuberculosis and related pathogens. In oxidative phosphorylation, the ETC establishes a transmembrane electrochemical proton gradient that powers ATP synthesis. Monitoring oxidative
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mRNA display reveals a class of high-affinity bromodomain-binding motifs that are not found in the human proteome J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-20 Jason K.K. Low, Karishma Patel, Natasha Jones, Paul Solomon, Alexander Norman, Joshua W.C. Maxwell, Petr Pachl, Jacqueline M. Matthews, Richard J. Payne, Toby Passioura, Hiroaki Suga, Louise J. Walport, Joel P. Mackay
Bromodomains regulate gene expression by recognizing protein motifs containing acetyllysine. Although originally characterized as histone-binding proteins, it has since become clear that these domains interact with other acetylated proteins, perhaps most prominently transcription factors. The likely transient nature and low stoichiometry of such modifications, however, has made it challenging to fully
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Metabolic reprogramming driven by EZH2 inhibition depends on cell-matrix interactions J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-20 Teresa W-M Fan, Jahid M.M. Islam, Richard M. Higashi, Penghui Lin, Christine F. Brainson, Andrew N. Lane
EZH2 (Enhancer of Zeste Homolog 2), a subunit of Polycomb Repressive Complex 2 (PRC2), catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3), which represses expression of genes. It also has PRC2-independent functions, including transcriptional coactivation of oncogenes, and is frequently overexpressed in lung cancers. Clinically, EZH2 inhibition can be achieved with the FDA-approved drug
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Singlet oxygen induces cell wall thickening and stomatal density reducing by transcriptome reprogramming J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-20 Zhong-Wei Zhang, Yu-Fan Fu, Xin-Yue Yang, Ming Yuan, Xiao-Jian Zheng, Xiao-Feng Luo, Meng-Yao Zhang, Lin-Bei Xie, Kai Shu, Steffen Reinbothe, Christiane Reinbothe, Fan Wu, Ling-Yang Feng, Jun-Bo Du, Chang-Quan Wang, Xue-Song Gao, Yang-Er Chen, Yan-Yan Zhang, Yang Li, Qi Tao, Shu Yuan
Singlet oxygen (1O2) has a very short half-life of 10−5 s; however, it is a strong oxidant that causes growth arrest and necrotic lesions on plants. Its signaling pathway remains largely unknown. The Arabidopsis flu (FLUORESCENT) mutant accumulates a high level of 1O2 and shows drastic changes in nuclear gene expression. Only two plastid proteins, EX1 (EXECUTER 1) and EX2 (EXECUTER 2), have been identified
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Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-18 Geetika Aggarwal, Subhashis Banerjee, Spencer A. Jones, Yousri Benchaar, Jasmine Bélanger, Myriam Sévigny, Denise M. Smith, Michael L. Niehoff, Monica Pavlack, Ian Mitchelle S. de Vera, Terri L. Petkau, Blair R. Leavitt, Karen Ling, Paymaan Jafar-Nejad, Frank Rigo, John E. Morley, Susan A. Farr, Paul A. Dutchak, Chantelle F. Sephton, Andrew D. Nguyen
Heterozygous GRN (progranulin) mutations cause frontotemporal dementia (FTD) due to haploinsufficiency, and increasing progranulin levels is a major therapeutic goal. Several microRNAs, including miR-29b, negatively regulate progranulin protein levels. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but strategies for increasing target protein
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Adipocyte-derived exosomal miR-22-3p modulated by circadian rhythm disruption regulates insulin sensitivity in skeletal muscle cells J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-18 Haohao Zhang, Xiaoning Zhang, Saifei Wang, Lu Zheng, Hengru Guo, Yanqi Ren, Bo Qiao, Jing Wu, Di Zhao, Lijun Xu, Shengnan Ma, Xiao Hao, Yushan Yan
Circadian rhythm disruption leads to dysregulation of lipid metabolism, which further drive the occurrence of insulin resistance (IR). Exosomes are natural carrier systems that advantageous for cell communication. In the present study, we aimed to explore whether and how the exosomal microRNAs (miRNAs) in circulation participate in modulating skeletal muscle IR induced by circadian rhythm disruption
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Cryo-EM structures of RNA polymerase II-nucleosome complexes rewrapping transcribed DNA J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-17 Munetaka Akatsu, Haruhiko Ehara, Tomoya Kujirai, Risa Fujita, Tomoko Ito, Ken Osumi, Mitsuo Ogasawara, Yoshimasa Takizawa, Shun-ichi Sekine, Hitoshi Kurumizaka
RNA polymerase II (RNAPII) transcribes DNA wrapped in the nucleosome by stepwise pausing, especially at nucleosomal superhelical locations -5 and -1 (SHL(-5) and SHL(-1), respectively). In the present study, we performed cryo-electron microscopy analyses of RNAPII-nucleosome complexes paused at a major nucleosomal pausing site, SHL(-1). We determined two previously undetected structures, in which the
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Identification and Characterization of Calreticulin as a Novel Plasminogen Receptor J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-17 Alamelu G. Bharadwaj, Gillian C. Okura, John W. Woods, Erica A. Allen, Victoria A. Miller, Emma Kempster, Mark A. Hancock, Shashi Gujar, Rimantas Slibinskas, David M. Waisman
Calreticulin (CRT) was originally identified as a key calcium-binding protein of the endoplasmic reticulum. Subsequently, CRT was shown to possess multiple intracellular functions, including roles in calcium homeostasis and protein folding. Recently, several extracellular functions have been identified for CRT, including roles in cancer cell invasion and phagocytosis of apoptotic and cancer cells by
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RecN spatially and temporally controls RecA-mediated repair of DNA double-strand breaks J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-17 Shunsuke Noda, Genki Akanuma, Kenji Keyamura, Takashi Hishida
RecN, a bacterial structural maintenance of chromosomes (SMC)-like protein, plays an important role in maintaining genomic integrity by facilitating the repair of DNA double-strand breaks (DSBs). However, how RecN-dependent chromosome dynamics are integrated with DSB repair remains unclear. Here, we investigated the dynamics of RecN in response to DNA damage by inducing RecN from the PBAD promoter
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Contribution of the yeast bi-chaperone system in the restoration of the RNA helicase Ded1 and translational activity under severe ethanol stress J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-17 Ryoko Ando, Yu Ishikawa, Yoshiaki Kamada, Shingo Izawa
Preexposure to mild stress often improves cellular tolerance to subsequent severe stress. Severe ethanol stress (10% v/v) causes persistent and pronounced translation repression in Saccharomyces cerevisiae. However, it remains unclear whether preexposure to mild stress can mitigate translation repression in yeast cells under severe ethanol stress. We found that the translational activity of yeast cells
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A gastrointestinal (GI) locally-activating Janus kinase (JAK) inhibitor to treat ulcerative colitis J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-17 Yingzi Bu, Mohamed Dit Mady Traore, Luchen Zhang, Lu Wang, Zhongwei Liu, Hongxiang Hu, Meilin Wang, Chengyi Li, Duxin Sun
In this study, we integrated machine learning (ML), structure-tissue selectivity-activity-relationship (STAR), - and wet lab synthesis/testing to design a gastrointestinal (GI) locally activating JAK inhibitor for ulcerative colitis treatment. The JAK inhibitor achieves site-specific efficacy through high local GI tissue selectivity, while minimizing the requirement for JAK isoform specificity to reduce
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Human V-ATPase a-subunit isoforms bind specifically to distinct phosphoinositide phospholipids J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-17 Connie Mitra, Samuel Winkley, Patricia M. Kane
V-ATPases are highly conserved multi-subunit enzymes that maintain the distinct pH of eukaryotic organelles. The integral membrane a-subunit is encoded by tissue- and organelle- specific isoforms, and its cytosolic N-terminal domain (aNT) modulates organelle specific regulation and targeting of V-ATPases. Organelle membranes have specific phosphatidylinositol phosphate (PIP) lipid enrichment linked
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STEADY-STATE REGULATION OF COPII-DEPENDENT SECRETORY CARGO SORTING BY INOSITOL TRISPHOSPHATE RECEPTORS, CALCIUM, AND PENTA EF HAND PROTEINS J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-17 Aaron Held, Jacob Lapka, John Sargeant, Jennet Hojanazarova, Alaa Shaheen, Samuel Galindo, Corina Madreiter-Sokolowski, Roland Malli, Wolfgang F. Graier, Jesse C. Hay
Recently, we demonstrated that agonist-stimulated Ca2+ signaling involving IP3 receptors modulates ER export rates through activation of the penta-EF Hand (PEF) proteins apoptosis-linked gene-2 (ALG-2) and peflin. It is unknown, however, whether IP3Rs and PEF proteins regulate ER export rates at steady state. Here we tested this idea in normal rat kidney (NRK) epithelial cells by manipulation of IP3R
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Mapping interactions of calmodulin and neuronal NO synthase by crosslinking and mass spectrometry J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-16 Dana Felker, Kanghyun Lee, Thomas H. Pospiech, Yoshihiro Morishima, Haoming Zhang, Miranda Lau, Daniel Southworth, Yoichi Osawa
Neuronal nitric oxide synthase (nNOS) is a homodimeric cytochrome P450-like enzyme that catalyzes the conversion of L-arginine to nitric oxide in the presence of NADPH and molecular oxygen. The binding of calmodulin (CaM) to a linker region between the FAD/FMN containing reductase domain and the heme containing oxygenase domain is needed for electron transfer reactions, reduction of the heme, and NO
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The Rax homeoprotein in Müller glial cells is required for homeostasis maintenance of the postnatal mouse retina J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-15 Takuya Yoshimoto, Taro Chaya, Leah R. Varner, Makoto Ando, Toshinori Tsujii, Daisuke Motooka, Kazuhiro Kimura, Takahisa Furukawa
Müller glial cells, which are the most predominant glial subtype in the retina, play multiple important roles, including the maintenance of structural integrity, homeostasis, and physiological functions of the retina. We have previously found that the Rax homeoprotein is expressed in postnatal and mature Müller glial cells in the mouse retina. However, the function of Rax in postnatal and mature Müller
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Collagen IV of basement membranes: II. Emergence of collagen IVα345 enabled the assembly of a compact GBM as an ultrafilter in mammalian kidneys J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-15 Elena N. Pokidysheva, Neve Redhair, Octavia Ailsworth, Patrick Page-McCaw, Louise Rollins-Smith, Vijayishwer Singh Jamwal, Yuko Ohta, Hans Peter Bächinger, Prayag Murawala, Martin Flajnik, Agnes B. Fogo, Dale Abrahamson, Julie K. Hudson, Sergei P. Boudko, Billy G. Hudson
The collagen IVα345 (Col-IVα345) scaffold, the major constituent of the glomerular basement membrane (GBM), is a critical component of the kidney glomerular filtration barrier. In chronic kidney disease, affecting hundreds of millions of people worldwide, over two thousand genetic variants occur in the COL4A3, COL4A4, and COL4A5 genes that encode the Col-IVα345 scaffold. Variants cause loss of scaffold
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Exosomes drive ferroptosis by stimulating iron accumulation to inhibit bacterial infection in crustaceans J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-15 Qian Sun, Jiawen Yang, Ming Zhang, Yongsheng Zhang, Hongyu Ma, Ngoc Tuan Tran, Xiuli Chen, Yueling Zhang, Kok-Gan Chan, Shengkang Li
Ferroptosis, characterized by iron-dependent cell death, has recently emerged as a critical defense mechanism against microbial infections. The present study aims to investigate the involvement of exosomes in the induction of ferroptosis and the inhibition of bacterial infection in crustaceans. Our findings provide compelling evidence for the pivotal role of exosomes in the immune response of crustaceans
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Mapping immunological and host receptor binding determinants of SARS-CoV spike protein utilizing the Qubevirus platform J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-15 Carrie Sanders, Aristide Dzelamonyuy, Augustin Ntemafack, Nadia Alatoom, Godwin Nchinda, Millie M. Georgiadis, Alain Bopda Waffo
The motifs involved in tropism and immunological interactions of SARS-CoV spike (S) protein were investigated utilizing the Qubevirus platform. We showed that separately, 14 overlapping peptide fragments representing the S protein (F1-14 of 100 residues each) could be inserted into the C-terminus of A1 on recombinant Qubevirus without affecting its viability. Additionally, recombinant phage expression
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c-Src regulates δ-secretase activation and truncated Tau production by phosphorylating the E3 ligase Traf6 J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-15 Yanli Jiang, Longfei Li, Ruozhen Wu, Liulin Wu, Bin Zhang, Jian-Zhi Wang, Rong Liu, Fei Liu, Jing Wang, Xiaochuan Wang
The accumulation of abnormal Tau protein is a common feature of various neurodegenerative diseases. Truncated Tau, resulting from cleavage by asparaginyl endopeptidase (AEP, δ-secretase), promotes its own phosphorylation and aggregation. Our study focused on understanding the regulatory mechanisms of AEP activation and its interaction with other proteins. We discovered that c-Src plays a critical role
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A complex with poly(A) binding protein and EWS facilitates the transcriptional function of oncogenic ETS transcription factors in prostate cells J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-11 Benjamin M. Greulich, Saranya Rajendran, Nicholas F. Downing, Taylor R. Nicholas, Peter C. Hollenhorst
The ETS transcription factor ERG is aberrantly expressed in approximately 50% of prostate tumors due to chromosomal rearrangements such as TMPRSS2/ERG. The ability of ERG to drive oncogenesis in prostate epithelial cells requires interaction with distinct co-activators, such as the RNA-binding protein EWS. Here, we find that ERG has both direct and indirect interactions with EWS, and the indirect interaction
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Characterization of erythroferrone oligomerization and its impact on BMP antagonism J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-09 Jacob F. Mast, Edmund AE. Leach, Thomas B. Thompson
Hepcidin, a peptide hormone that negatively regulates iron metabolism, is expressed by bone morphogenetic protein (BMP) signaling. Erythroferrone (ERFE) is an extracellular protein that binds and inhibits BMP ligands, thus positively regulating iron import by indirectly suppressing hepcidin. This allows for rapid erythrocyte regeneration after blood loss. ERFE belongs to the C1Q/TNF related protein
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Regulatory mechanisms of one-carbon metabolism enzymes J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-09 Boryana Petrova, Adam G. Maynard, Peng Wang, Naama Kanarek
One-carbon metabolism is a central metabolic pathway critical for the biosynthesis of several amino acids, methyl group donors, and nucleotides. The pathway mostly relies on the transfer of a carbon unit from the amino acid serine, through the cofactor folate (in its several forms), and to the ultimate carbon acceptors that include nucleotides and methyl groups used for methylation of proteins, RNA
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Structure of Phosphorylated-like RssB, the Adaptor Delivering σs to the ClpXP Proteolytic Machinery, Reveals an Interface Switch for Activation J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-09 Christiane Brugger, Jacob Schwartz, Scott Novick, Song Tong, Joel Hoskins, Nadim Majdalani, Rebecca Kim, Martin Filipovski, Sue Wickner, Susan Gottesman, Patrick Griffin, Alexandra M. Deaconescu
In enterobacteria such as Escherichia coli, the general stress response is mediated by σs, the stationary phase dissociable promoter specificity subunit of RNA polymerase. σs is degraded by ClpXP during active growth in a process dependent on the RssB adaptor, which is thought to be stimulated by phosphorylation of a conserved aspartate in its N-terminal receiver domain. Here we present the crystal
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TTC17 is an endoplasmic reticulum resident TPR-containing adaptor protein J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-08 Nathan P. Canniff, Jill B. Graham, Kevin P. Guay, Daniel A. Lubicki, Stephen J. Eyles, Jennifer N. Rauch, Daniel N. Hebert
Protein folding, quality control, maturation, and trafficking are essential processes for proper cellular homeostasis. Around one third of the human proteome is targeted to the endoplasmic reticulum (ER), the organelle that serves as entrance into the secretory pathway. Successful protein trafficking is paramount for proper cellular function and to that end there are many ER resident proteins that
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Resolving Binding Pathways and Solvation Thermodynamics of Plant Hormone Receptors J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-08 Chuankai Zhao, Diego E. Kleiman, Diwakar Shukla
Plant hormones are small molecules that regulate plant growth, development, and responses to biotic and abiotic stresses. They are specifically recognized by the binding site of their receptors. In this work, we resolved the binding pathways for eight classes of phytohormones (auxin, jasmonate, gibberellin, strigolactone, brassinosteroid, cytokinin, salicylic acid, and abscisic acid) to their canonical
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Developing Multi-Species Quorum Sensing Modulators Based on the Streptococcus mitis Competence-Stimulating Peptide J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-10 Tahmina A. Milly, Clay P. Renshaw, Yftah Tal-Gan
Bacteria utilize quorum sensing (QS) to coordinate many group behaviors. As such, QS has attracted significant attention as a potential mean to attenuate bacterial infectivity without introducing selective pressure for resistance development. Streptococcus mitis, a human commensal, acts as a genetic diversity reservoir for Streptococcus pneumoniae, a prevalent human pathogen. S. mitis possesses a typical
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Functional characterization of the CRY2 circadian clock component variant p.Ser420Phe revealed a new degradation pathway for CRY2 J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-10 Gizem Cagla Parlak, Ibrahim Baris, Seref Gul, Ibrahim Halil Kavakli
Cryptochromes (CRYs) are essential components of the circadian clock, playing a pivotal role as transcriptional repressors. Despite their significance, the precise mechanisms underlying CRYs' involvement in the circadian clock remain incompletely understood. In this study, we identified a rare CRY2 variant, p.Ser420Phe, from the 1000 Genomes Project and Ensembl database that is located in the functionally
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Adenine base editor-mediated splicing remodeling activates non-canonical splice sites J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-09 Yuanyuan Liu, Qing Li, Tong Yan, Haoran Chen, Jiahua Wang, Yingyi Wang, Yeqin Yang, Lue Xiang, Zailong Chi, Kaiqun Ren, Bin Lin, Ge Lin, Jinsong Li, Yong Liu, Feng Gu
Adenine base editors (ABEs) are genome-editing tools that have been harnessed to introduce precise A•T to G•C conversion. The discovery of split genes revealed that all introns contain two highly conserved dinucleotides, canonical “AG” (acceptor) and “GT” (donor) splice sites. ABE can directly edit splice acceptor sites of the adenine (A) base, leading to aberrant gene splicing, which may be further
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Disease-causing cystathionine β-synthase linker mutations impair allosteric regulation J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-08 Joseph V. Roman, Romila Mascarenhas, Karanfil Ceric, David P. Ballou, Ruma Banerjee
Cystathionine β-synthase (CBS) catalyzes the committing step in the transsulfuration pathway, which is important for clearing homocysteine and furnishing cysteine. The transsulfuration pathway also generates H2S, a signaling molecule. CBS is a modular protein with a heme and pyridoxal phosphate-binding catalytic core, which is separated by a linker region from the C-terminal regulatory domain that
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Phosphate uptake restriction, phosphate export, and polyphosphate synthesis contribute synergistically to cellular proliferation and survival J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-08 Masahiro Takado, Tochi Komamura, Tomoki Nishimura, Ikkei Ohkubo, Keita Ohuchi, Tomohiro Matsumoto, Kojiro Takeda
Phosphate (Pi) is a macronutrient, and Pi homeostasis is essential for life. Pi homeostasis has been intensively studied; however, many questions remain, even at the cellular level. Using Schizosaccharomyces pombe, we sought to better understand cellular Pi homeostasis and showed that three Pi regulators with SPX domains, Xpr1/Spx2, Pqr1, and the VTC complex synergistically contribute to Pi homeostasis
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Cardioprotective O-GlcNAc-Signaling is Elevated in Murine Female Hearts via Enhanced O-GlcNAc Transferase Activity J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-08 Bhargavi Narayanan, Prithvi Sinha, Roger Henry, Russell A. Reeves, Nazareno Paolocci, Mark J. Kohr, Natasha E. Zachara
The post-translational modification of intracellular proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) has emerged as a critical regulator of cardiac function. Enhanced O-GlcNAcylation activates cytoprotective pathways in cardiac models of ischemia reperfusion (I/R) injury; however, the mechanisms underpinning O-GlcNAc-cycling in response to I/R injury have not been comprehensively assessed. The
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tRNA m1G9 modification depends on substrate-specific RNA conformational changes induced by the methyltransferase Trm10 J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-08 Sarah E. Strassler, Isobel E. Bowles, Aiswarya Krishnamohan, Hyejeong Kim, Catherine B. Edgington, Emily G. Kuiper, Clio J. Hancock, Lindsay R. Comstock, Jane E. Jackman, Graeme L. Conn
The methyltransferase Trm10 modifies a subset of tRNAs on the base N1 position of the 9th nucleotide in the tRNA core. Trm10 is conserved throughout Eukarya and Archaea, and mutations in the human gene (TRMT10A) have been linked to neurological disorders such as microcephaly and intellectual disability, as well as defects in glucose metabolism. Of the 26 tRNAs in yeast with guanosine at position 9
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Sterol Activated Amyloid Beta Fibril Formation J. Biol. Chem. (IF 5.5) Pub Date : 2023-11-08 Ian Cook, Thomas S. Leyh
The metabolic processes that link Alzheimer’s disease (AD) to elevated cholesterol levels in the brain are not fully defined. Amyloid beta (Aβ) plaque accumulation is believed to begin decades prior to symptoms and to contribute significantly to the disease. Cholesterol and its metabolites accelerate plaque formation through as-yet undefined mechanisms. Here, the mechanism of cholesterol (CH) and cholesterol