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Calmodulin Mutations Associated with Heart Arrhythmia: A Status Report.
Chazin WJ, Johnson CN
(2020) Int J Mol Sci 21:
MeSH Terms: Arrhythmias, Cardiac, Calcium Signaling, Calmodulin, Humans, Ion Channels, Long QT Syndrome, Myocytes, Cardiac, Ryanodine Receptor Calcium Release Channel, Tachycardia, Ventricular
Show Abstract · Added March 11, 2020
Calmodulin (CaM) is a ubiquitous intracellular Ca sensing protein that modifies gating of numerous ion channels. CaM has an extraordinarily high level of evolutionary conservation, which led to the fundamental assumption that mutation would be lethal. However, in 2012, complete exome sequencing of infants suffering from recurrent cardiac arrest revealed de novo mutations in the three human genes. The correlation between mutations and pathophysiology suggests defects in CaM-dependent ion channel functions. Here, we review the current state of the field for all reported CaM mutations associated with cardiac arrhythmias, including knowledge of their biochemical and structural characteristics, and progress towards understanding how these mutations affect cardiac ion channel function.
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9 MeSH Terms
Cryo-EM structure of human type-3 inositol triphosphate receptor reveals the presence of a self-binding peptide that acts as an antagonist.
Azumaya CM, Linton EA, Risener CJ, Nakagawa T, Karakas E
(2020) J Biol Chem 295: 1743-1753
MeSH Terms: Binding Sites, Calcium Signaling, Cryoelectron Microscopy, Humans, Inositol 1,4,5-Trisphosphate, Inositol 1,4,5-Trisphosphate Receptors, Models, Molecular, Peptides, Protein Conformation
Show Abstract · Added March 3, 2020
Calcium-mediated signaling through inositol 1,4,5-triphosphate receptors (IPRs) is essential for the regulation of numerous physiological processes, including fertilization, muscle contraction, apoptosis, secretion, and synaptic plasticity. Deregulation of IPRs leads to pathological calcium signaling and is implicated in many common diseases, including cancer and neurodegenerative, autoimmune, and metabolic diseases. Revealing the mechanism of activation and inhibition of this ion channel will be critical to an improved understanding of the biological processes that are controlled by IPRs. Here, we report structural findings of the human type-3 IPR (IPR-3) obtained by cryo-EM (at an overall resolution of 3.8 Å), revealing an unanticipated regulatory mechanism where a loop distantly located in the primary sequence occupies the IP-binding site and competitively inhibits IP binding. We propose that this inhibitory mechanism must differ qualitatively among IPR subtypes because of their diverse loop sequences, potentially serving as a key molecular determinant of subtype-specific calcium signaling in IPRs. In summary, our structural characterization of human IPR-3 provides critical insights into the mechanistic function of IPRs and into subtype-specific regulation of these important calcium-regulatory channels.
© 2020 Azumaya et al.
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9 MeSH Terms
Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core.
Tian J, Teuscher KB, Aho ER, Alvarado JR, Mills JJ, Meyers KM, Gogliotti RD, Han C, Macdonald JD, Sai J, Shaw JG, Sensintaffar JL, Zhao B, Rietz TA, Thomas LR, Payne WG, Moore WJ, Stott GM, Kondo J, Inoue M, Coffey RJ, Tansey WP, Stauffer SR, Lee T, Fesik SW
(2020) J Med Chem 63: 656-675
MeSH Terms: Antineoplastic Agents, Bridged Bicyclo Compounds, Heterocyclic, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Chromatin, Crystallography, X-Ray, Drug Design, Drug Discovery, Epigenetic Repression, Genes, myc, Humans, Intracellular Signaling Peptides and Proteins, Quinolones, Structure-Activity Relationship, WD40 Repeats
Show Abstract · Added March 3, 2020
WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple chromatin-centric processes. Overexpression of WDR5 correlates with a poor clinical outcome in many human cancers, and WDR5 itself has emerged as an attractive target for therapy. Most drug-discovery efforts center on the WIN site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe discovery of a novel WDR5 WIN site antagonists containing a dihydroisoquinolinone bicyclic core using a structure-based design. These compounds exhibit picomolar binding affinity and selective concentration-dependent antiproliferative activities in sensitive MLL-fusion cell lines. Furthermore, these WDR5 WIN site binders inhibit proliferation in MYC-driven cancer cells and reduce MYC recruitment to chromatin at MYC/WDR5 co-bound genes. Thus, these molecules are useful probes to study the implication of WDR5 inhibition in cancers and serve as a potential starting point toward the discovery of anti-WDR5 therapeutics.
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16 MeSH Terms
BRAF molecular testing in cytopathology: Implications for diagnosis, prognosis, and targeted therapeutics.
Bergdorf KN, Lee LA, Weiss VL
(2020) Cancer Cytopathol 128: 9-11
MeSH Terms: Antineoplastic Agents, Genetic Testing, Humans, MAP Kinase Signaling System, Molecular Targeted Therapy, Mutation, Neoplasms, Phosphorylation, Precision Medicine, Prognosis, Proto-Oncogene Proteins B-raf
Added March 3, 2020
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11 MeSH Terms
Nod-like receptors are critical for gut-brain axis signalling in mice.
Pusceddu MM, Barboza M, Keogh CE, Schneider M, Stokes P, Sladek JA, Kim HJD, Torres-Fuentes C, Goldfild LR, Gillis SE, Brust-Mascher I, Rabasa G, Wong KA, Lebrilla C, Byndloss MX, Maisonneuve C, Bäumler AJ, Philpott DJ, Ferrero RL, Barrett KE, Reardon C, Gareau MG
(2019) J Physiol 597: 5777-5797
MeSH Terms: Animals, Anxiety, Brain, Cells, Cultured, Cognition, Female, Hypothalamo-Hypophyseal System, Intestinal Absorption, Intestinal Mucosa, Male, Mice, Mice, Inbred C57BL, Neurogenesis, Nod1 Signaling Adaptor Protein, Nod2 Signaling Adaptor Protein, Serotonin, Stress, Psychological, Synaptic Transmission
Show Abstract · Added March 30, 2020
KEY POINTS - •Nucleotide binding oligomerization domain (Nod)-like receptors regulate cognition, anxiety and hypothalamic-pituitary-adrenal axis activation. •Nod-like receptors regulate central and peripheral serotonergic biology. •Nod-like receptors are important for maintenance of gastrointestinal physiology. •Intestinal epithelial cell expression of Nod1 receptors regulate behaviour.
ABSTRACT - Gut-brain axis signalling is critical for maintaining health and homeostasis. Stressful life events can impact gut-brain signalling, leading to altered mood, cognition and intestinal dysfunction. In the present study, we identified nucleotide binding oligomerization domain (Nod)-like receptors (NLR), Nod1 and Nod2, as novel regulators for gut-brain signalling. NLR are innate immune pattern recognition receptors expressed in the gut and brain, and are important in the regulation of gastrointestinal physiology. We found that mice deficient in both Nod1 and Nod2 (NodDKO) demonstrate signs of stress-induced anxiety, cognitive impairment and depression in the context of a hyperactive hypothalamic-pituitary-adrenal axis. These deficits were coupled with impairments in the serotonergic pathway in the brain, decreased hippocampal cell proliferation and immature neurons, as well as reduced neural activation. In addition, NodDKO mice had increased gastrointestinal permeability and altered serotonin signalling in the gut following exposure to acute stress. Administration of the selective serotonin reuptake inhibitor, fluoxetine, abrogated behavioural impairments and restored serotonin signalling. We also identified that intestinal epithelial cell-specific deletion of Nod1 (VilCre Nod1 ), but not Nod2, increased susceptibility to stress-induced anxiety-like behaviour and cognitive impairment following exposure to stress. Together, these data suggest that intestinal epithelial NLR are novel modulators of gut-brain communication and may serve as potential novel therapeutic targets for the treatment of gut-brain disorders.
© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.
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18 MeSH Terms
Normal Saline solutions cause endothelial dysfunction through loss of membrane integrity, ATP release, and inflammatory responses mediated by P2X7R/p38 MAPK/MK2 signaling pathways.
Cheung-Flynn J, Alvis BD, Hocking KM, Guth CM, Luo W, McCallister R, Chadalavada K, Polcz M, Komalavilas P, Brophy CM
(2019) PLoS One 14: e0220893
MeSH Terms: Adenosine Triphosphate, Animals, Aorta, Cell Membrane, Endothelial Cells, Humans, Inflammation, Intracellular Signaling Peptides and Proteins, Phosphorylation, Protein-Serine-Threonine Kinases, Rats, Receptors, Purinergic P2X7, Saline Solution, Saphenous Vein, Signal Transduction, Swine, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added March 3, 2020
Resuscitation with 0.9% Normal Saline (NS), a non-buffered acidic solution, leads to increased morbidity and mortality in the critically ill. The goal of this study was to determine the molecular mechanisms of endothelial injury after exposure to NS. The hypothesis of this investigation is that exposure of endothelium to NS would lead to loss of cell membrane integrity, resulting in release of ATP, activation of the purinergic receptor (P2X7R), and subsequent activation of stress activated signaling pathways and inflammation. Human saphenous vein endothelial cells (HSVEC) incubated in NS, but not buffered electrolyte solution (Plasma-Lyte, PL), exhibited abnormal morphology and increased release of lactate dehydrogenase (LDH), adenosine triphosphate (ATP), and decreased transendothelial resistance (TEER), suggesting loss of membrane integrity. Incubation of intact rat aorta (RA) or human saphenous vein in NS but not PL led to impaired endothelial-dependent relaxation which was ameliorated by apyrase (hydrolyzes ATP) or SB203580 (p38 MAPK inhibitor). Exposure of HSVEC to NS but not PL led to activation of p38 MAPK and its downstream substrate, MAPKAP kinase 2 (MK2). Treatment of HSVEC with exogenous ATP led to interleukin 1β (IL-1β) release and increased vascular cell adhesion molecule (VCAM) expression. Treatment of RA with IL-1β led to impaired endothelial relaxation. IL-1β treatment of HSVEC led to increases in p38 MAPK and MK2 phosphorylation, and increased levels of arginase II. Incubation of porcine saphenous vein (PSV) in PL with pH adjusted to 6.0 or less also led to impaired endothelial function, suggesting that the acidic nature of NS is what contributes to endothelial dysfunction. Volume overload resuscitation in a porcine model after hemorrhage with NS, but not PL, led to acidosis and impaired endothelial function. These data suggest that endothelial dysfunction caused by exposure to acidic, non-buffered NS is associated with loss of membrane integrity, release of ATP, and is modulated by P2X7R-mediated inflammatory responses.
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17 MeSH Terms
Brucella abortus Infection of Placental Trophoblasts Triggers Endoplasmic Reticulum Stress-Mediated Cell Death and Fetal Loss via Type IV Secretion System-Dependent Activation of CHOP.
Byndloss MX, Tsai AY, Walker GT, Miller CN, Young BM, English BC, Seyffert N, Kerrinnes T, de Jong MF, Atluri VL, Winter MG, Celli J, Tsolis RM
(2019) mBio 10:
MeSH Terms: Animals, Brucella abortus, Cell Death, Endoplasmic Reticulum Stress, Female, Mice, Mice, Inbred C57BL, Nod1 Signaling Adaptor Protein, Nod2 Signaling Adaptor Protein, Placenta, Pregnancy, Transcription Factor CHOP, Trophoblasts, Type IV Secretion Systems, Unfolded Protein Response
Show Abstract · Added March 30, 2020
Subversion of endoplasmic reticulum (ER) function is a feature shared by multiple intracellular bacteria and viruses, and in many cases this disruption of cellular function activates pathways of the unfolded protein response (UPR). In the case of infection with , the etiologic agent of brucellosis, the unfolded protein response in the infected placenta contributes to placentitis and abortion, leading to pathogen transmission. Here we show that infection of pregnant mice led to death of infected placental trophoblasts in a manner that depended on the VirB type IV secretion system (T4SS) and its effector VceC. The trophoblast death program required the ER stress-induced transcription factor CHOP. While NOD1/NOD2 expression in macrophages contributed to ER stress-induced inflammation, these receptors did not play a role in trophoblast death. Both placentitis and abortion were independent of apoptosis-associated Speck-like protein containing a caspase activation and recruitment domain (ASC). These studies show that uses its T4SS to induce cell-type-specific responses to ER stress in trophoblasts that trigger placental inflammation and abortion. Our results suggest further that in the T4SS and its effectors are under selection as bacterial transmission factors. infects the placenta of pregnant cows, where it replicates to high levels and triggers abortion of the calf. The aborted material is highly infectious and transmits infection to both cows and humans, but very little is known about how causes abortion. By studying this infection in pregnant mice, we discovered that kills trophoblasts, which are important cells for maintaining pregnancy. This killing required an injected bacterial protein (VceC) that triggered an endoplasmic reticulum (ER) stress response in the trophoblast. By inhibiting ER stress or infecting mice that lack CHOP, a protein induced by ER stress, we could prevent death of trophoblasts, reduce inflammation, and increase the viability of the pups. Our results suggest that injects VceC into placental trophoblasts to promote its transmission by abortion.
Copyright © 2019 Byndloss et al.
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15 MeSH Terms
Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations.
Ahmed IA, Farooqi MS, Vander Lugt MT, Boklan J, Rose M, Friehling ED, Triplett B, Lieuw K, Saldana BD, Smith CM, Schwartz JR, Goyal RK
(2019) Biol Blood Marrow Transplant 25: 2186-2196
MeSH Terms: Allografts, Child, Preschool, Disease-Free Survival, Female, Genetic Diseases, Inborn, Germ-Line Mutation, Hematopoietic Stem Cell Transplantation, Humans, Infant, Intracellular Signaling Peptides and Proteins, Male, Myelodysplastic Syndromes, Retrospective Studies, Survival Rate, Syndrome, Tumor Suppressor Proteins
Show Abstract · Added September 19, 2019
Germline mutations in SAMD9 and SAMD9L genes cause MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) (OMIM: *610456) and ataxia-pancytopenia (OMIM: *611170) syndromes, respectively, and are associated with chromosome 7 deletions, myelodysplastic syndrome (MDS), and bone marrow failure. In this retrospective series, we report outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with hematologic disorders associated with SAMD9/SAMD9L mutations. Twelve patients underwent allogeneic HCT for MDS (n = 10), congenital amegakaryocytic thrombocytopenia (n = 1), and dyskeratosis congenita (n = 1). Exome sequencing revealed heterozygous mutations in SAMD9 (n = 6) or SAMD9L (n = 6) genes. Four SAMD9 patients had features of MIRAGE syndrome. Median age at HCT was 2.8 years (range, 1.2 to 12.8 years). Conditioning was myeloablative in 9 cases and reduced intensity in 3 cases. Syndrome-related comorbidities (diarrhea, infections, adrenal insufficiency, malnutrition, and electrolyte imbalance) were present in MIRAGE syndrome cases. One patient with a familial SAMD9L mutation, MDS, and morbid obesity failed to engraft and died of refractory acute myeloid leukemia. The other 11 patients achieved neutrophil engraftment. Acute post-transplant course was complicated by syndrome-related comorbidities in MIRAGE cases. A patient with SAMD9L-associated MDS died of diffuse alveolar hemorrhage. The other 10 patients had resolution of hematologic disorder and sustained peripheral blood donor chimerism. Ten of 12 patients were alive with a median follow-up of 3.1 years (range, 0.1 to 14.7 years). More data are needed to refine transplant approaches in SAMD9/SAMD9L patients with significant comorbidities and to develop guidelines for their long-term follow-up.
Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.
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16 MeSH Terms
Single-Cell Analyses Confirm the Critical Role of LRP6 for Wnt Signaling in APC-Deficient Cells.
Cabel CR, Alizadeh E, Robbins DJ, Ahmed Y, Lee E, Thorne CA
(2019) Dev Cell 49: 827-828
MeSH Terms: Clathrin, Low Density Lipoprotein Receptor-Related Protein-6, Single-Cell Analysis, Wnt Signaling Pathway
Added July 23, 2019
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4 MeSH Terms
Developmental regulation of Wnt signaling by Nagk and the UDP-GlcNAc salvage pathway.
Neitzel LR, Spencer ZT, Nayak A, Cselenyi CS, Benchabane H, Youngblood CQ, Zouaoui A, Ng V, Stephens L, Hann T, Patton JG, Robbins D, Ahmed Y, Lee E
(2019) Mech Dev 156: 20-31
MeSH Terms: Animals, Body Patterning, Drosophila, Embryonic Development, Evolution, Molecular, Gene Expression Regulation, Developmental, Glycosylation, Humans, Phosphotransferases (Alcohol Group Acceptor), Wnt Signaling Pathway, Xenopus laevis, Zebrafish
Show Abstract · Added April 10, 2019
In a screen for human kinases that regulate Xenopus laevis embryogenesis, we identified Nagk and other components of the UDP-GlcNAc glycosylation salvage pathway as regulators of anteroposterior patterning and Wnt signaling. We find that the salvage pathway does not affect other major embryonic signaling pathways (Fgf, TGFβ, Notch, or Shh), thereby demonstrating specificity for Wnt signaling. We show that the role of the salvage pathway in Wnt signaling is evolutionarily conserved in zebrafish and Drosophila. Finally, we show that GlcNAc is essential for the growth of intestinal enteroids, which are highly dependent on Wnt signaling for growth and maintenance. We propose that the Wnt pathway is sensitive to alterations in the glycosylation state of a cell and acts as a nutritional sensor in order to couple growth/proliferation with its metabolic status. We also propose that the clinical manifestations observed in congenital disorders of glycosylation (CDG) in humans may be due, in part, to their effects on Wnt signaling during development.
Copyright © 2019 Elsevier B.V. All rights reserved.
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12 MeSH Terms