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The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation.
Fischer K, Fenzl A, Liu D, Dyar KA, Kleinert M, Brielmeier M, Clemmensen C, Fedl A, Finan B, Gessner A, Jastroch M, Huang J, Keipert S, Klingenspor M, Brüning JC, Kneilling M, Maier FC, Othman AE, Pichler BJ, Pramme-Steinwachs I, Sachs S, Scheideler A, Thaiss WM, Uhlenhaut H, Ussar S, Woods SC, Zorn J, Stemmer K, Collins S, Diaz-Meco M, Moscat J, Tschöp MH, Müller TD
(2020) Nat Commun 11: 2306
MeSH Terms: Activating Transcription Factor 2, Adipogenesis, Adipose Tissue, Brown, Adipose Tissue, White, Animals, Cell Nucleus, Magnetic Resonance Imaging, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Positron Emission Tomography Computed Tomography, Protein Binding, Sequestosome-1 Protein, Uncoupling Protein 1, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added July 22, 2020
During β-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1α. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activation of the Ucp1 enhancer and Pgc-1α promoter. P62 mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1α expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62 mice, global p62 and Ucp1-Cre p62 mice. BAT dysfunction resulting from p62 deficiency is manifest after birth and obesity subsequently develops despite normal food intake, intestinal nutrient absorption and locomotor activity. In summary, our data identify p62 as a master regulator of BAT function in that it controls the Ucp1 pathway through regulation of ATF2 genomic binding.
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18 MeSH Terms
Gene network transitions in embryos depend upon interactions between a pioneer transcription factor and core histones.
Iwafuchi M, Cuesta I, Donahue G, Takenaka N, Osipovich AB, Magnuson MA, Roder H, Seeholzer SH, Santisteban P, Zaret KS
(2020) Nat Genet 52: 418-427
MeSH Terms: Amino Acid Sequence, Animals, Cell Line, Chromatin, DNA, Female, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Histones, Humans, Mice, Mice, Inbred C57BL, Nucleosomes, Transcription Factors, Transcription, Genetic
Show Abstract · Added April 7, 2020
Gene network transitions in embryos and other fate-changing contexts involve combinations of transcription factors. A subset of fate-changing transcription factors act as pioneers; they scan and target nucleosomal DNA and initiate cooperative events that can open the local chromatin. However, a gap has remained in understanding how molecular interactions with the nucleosome contribute to the chromatin-opening phenomenon. Here we identified a short α-helical region, conserved among FOXA pioneer factors, that interacts with core histones and contributes to chromatin opening in vitro. The same domain is involved in chromatin opening in early mouse embryos for normal development. Thus, local opening of chromatin by interactions between pioneer factors and core histones promotes genetic programming.
1 Communities
3 Members
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15 MeSH Terms
PEGylated PLGA Nanoparticle Delivery of Eggmanone for T Cell Modulation: Applications in Rheumatic Autoimmunity.
Haycook CP, Balsamo JA, Glass EB, Williams CH, Hong CC, Major AS, Giorgio TD
(2020) Int J Nanomedicine 15: 1215-1228
MeSH Terms: Animals, Autoimmunity, CD4-Positive T-Lymphocytes, Cytokines, Drug Delivery Systems, Female, Hedgehog Proteins, Immunoglobulin Fragments, Immunologic Factors, Mice, Inbred C57BL, Nanoparticles, Polylactic Acid-Polyglycolic Acid Copolymer, Pyrimidinones, Rheumatic Diseases, T-Lymphocytes, T-Lymphocytes, Helper-Inducer, Thiophenes
Show Abstract · Added March 30, 2020
Background - Helper T cell activity is dysregulated in a number of diseases including those associated with rheumatic autoimmunity. Treatment options are limited and usually consist of systemic immune suppression, resulting in undesirable consequences from compromised immunity. Hedgehog (Hh) signaling has been implicated in the activation of T cells and the formation of the immune synapse, but remains understudied in the context of autoimmunity. Modulation of Hh signaling has the potential to enable controlled immunosuppression but a potential therapy has not yet been developed to leverage this opportunity.
Methods - In this work, we developed biodegradable nanoparticles to enable targeted delivery of eggmanone (Egm), a specific Hh inhibitor, to CD4 T cell subsets. We utilized two FDA-approved polymers, poly(lactic-co-glycolic acid) and polyethylene glycol, to generate hydrolytically degradable nanoparticles. Furthermore, we employed maleimide-thiol mediated conjugation chemistry to decorate nanoparticles with anti-CD4 F(ab') antibody fragments to enable targeted delivery of Egm.
Results - Our novel delivery system achieved a highly specific association with the majority of CD4 T cells present among a complex cell population. Additionally, we have demonstrated antigen-specific inhibition of CD4 T cell responses mediated by nanoparticle-formulated Egm.
Conclusion - This work is the first characterization of Egm's immunomodulatory potential. Importantly, this study also suggests the potential benefit of a biodegradable delivery vehicle that is rationally designed for preferential interaction with a specific immune cell subtype for targeted modulation of Hh signaling.
© 2020 Haycook et al.
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17 MeSH Terms
Osteopontin and iCD8α Cells Promote Intestinal Intraepithelial Lymphocyte Homeostasis.
Nazmi A, Greer MJ, Hoek KL, Piazuelo MB, Weitkamp JH, Olivares-Villagómez D
(2020) J Immunol 204: 1968-1981
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Epithelium, Female, Homeostasis, Humans, Hyaluronan Receptors, Intestines, Intraepithelial Lymphocytes, Killer Cells, Natural, Male, Mice, Mice, Inbred C57BL, Osteopontin, Receptors, Antigen, T-Cell, gamma-delta, Th17 Cells
Show Abstract · Added February 28, 2020
Intestinal intraepithelial lymphocytes (IEL) comprise a diverse population of cells residing in the epithelium at the interface between the intestinal lumen and the sterile environment of the lamina propria. Because of this anatomical location, IEL are considered critical components of intestinal immune responses. Indeed, IEL are involved in many different immunological processes, ranging from pathogen control to tissue stability. However, despite their critical importance in mucosal immune responses, very little is known about the homeostasis of different IEL subpopulations. The phosphoprotein osteopontin is important for critical physiological processes, including cellular immune responses, such as survival of Th17 cells and homeostasis of NK cells among others. Because of its impact in the immune system, we investigated the role of osteopontin in the homeostasis of IEL. In this study, we report that mice deficient in the expression of osteopontin exhibit reduced numbers of the IEL subpopulations TCRγδ, TCRβCD4, TCRβCD4CD8α, and TCRβCD8αα cells in comparison with wild-type mice. For some IEL subpopulations, the decrease in cell numbers could be attributed to apoptosis and reduced cell division. Moreover, we show in vitro that exogenous osteopontin stimulates the survival of murine IEL subpopulations and unfractionated IEL derived from human intestines, an effect mediated by CD44, a known osteopontin receptor. We also show that iCD8α IEL but not TCRγδ IEL, TCRβ IEL, or intestinal epithelial cells, can promote survival of different IEL populations via osteopontin, indicating an important role for iCD8α cells in the homeostasis of IEL.
Copyright © 2020 by The American Association of Immunologists, Inc.
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17 MeSH Terms
Development of a novel murine model of lymphatic metastasis.
Banan B, Beckstead JA, Dunavant LE, Sohn Y, Adcock JM, Nomura S, Abumrad N, Goldenring JR, Fingleton B
(2020) Clin Exp Metastasis 37: 247-255
MeSH Terms: Animals, Cell Line, Tumor, Colonic Neoplasms, Disease Models, Animal, Female, Green Fluorescent Proteins, Humans, Luciferases, Luminescent Measurements, Lymph Nodes, Lymphatic Metastasis, Lymphatic Vessels, Male, Mesentery, Mice, Mice, Inbred C57BL, Stomach Neoplasms, Tomography, Optical, Tumor Burden
Show Abstract · Added March 24, 2020
Current laboratory models of lymphatic metastasis generally require either genetically modified animals or are technically challenging. Herein, we have developed a robust protocol for the induction of intralymphatic metastasis in wild-type mice with reproducible outcomes. To determine an optimal injection quantity and timeline for tumorigenesis, C57Bl/6 mice were injected directly into the mesenteric lymph duct (MLD) with varying numbers of syngeneic murine colon cancer cells (MC38) or gastric cancer cells (YTN16) expressing GFP/luciferase and monitored over 2-4 weeks. Tumor growth was tracked via whole-animal in vivo bioluminescence imaging (IVIS). Our data indicate that the injection of tumor cells into the MLD is a viable model for lymphatic metastasis as necropsies revealed large tumor burdens and metastasis in regional lymph nodes. This protocol enables a closer study of the role of lymphatics in cancer metastasis and opens a window for the development of novel approaches for treatment of metastatic diseases.
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19 MeSH Terms
Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel CaMKIIα-Shank3 Interaction.
Perfitt TL, Wang X, Dickerson MT, Stephenson JR, Nakagawa T, Jacobson DA, Colbran RJ
(2020) J Neurosci 40: 2000-2014
MeSH Terms: Animals, Calcium Channels, L-Type, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cell Nucleus, Gene Expression Regulation, Hippocampus, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins, Neurons, Signal Transduction
Show Abstract · Added March 3, 2020
The activation of neuronal plasma membrane Ca channels stimulates many intracellular responses. Scaffolding proteins can preferentially couple specific Ca channels to distinct downstream outputs, such as increased gene expression, but the molecular mechanisms that underlie the exquisite specificity of these signaling pathways are incompletely understood. Here, we show that complexes containing CaMKII and Shank3, a postsynaptic scaffolding protein known to interact with L-type calcium channels (LTCCs), can be specifically coimmunoprecipitated from mouse forebrain extracts. Activated purified CaMKIIα also directly binds Shank3 between residues 829 and 1130. Mutation of Shank3 residues Arg-Arg-Lys to three alanines disrupts CaMKII binding and CaMKII association with Shank3 in heterologous cells. Our shRNA/rescue studies revealed that Shank3 binding to both CaMKII and LTCCs is important for increased phosphorylation of the nuclear CREB transcription factor and expression of c-Fos induced by depolarization of cultured hippocampal neurons. Thus, this novel CaMKII-Shank3 interaction is essential for the initiation of a specific long-range signal from LTCCs in the plasma membrane to the nucleus that is required for activity-dependent changes in neuronal gene expression during learning and memory. Precise neuronal expression of genes is essential for normal brain function. Proteins involved in signaling pathways that underlie activity-dependent gene expression, such as CaMKII, Shank3, and L-type calcium channels, are often mutated in multiple neuropsychiatric disorders. Shank3 and CaMKII were previously shown to bind L-type calcium channels, and we show here that Shank3 also binds to CaMKII. Our data show that each of these interactions is required for depolarization-induced phosphorylation of the CREB nuclear transcription factor, which stimulates the expression of c-Fos, a neuronal immediate early gene with key roles in synaptic plasticity, brain development, and behavior.
Copyright © 2020 the authors.
1 Communities
1 Members
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11 MeSH Terms
Cell-free hemoglobin increases inflammation, lung apoptosis, and microvascular permeability in murine polymicrobial sepsis.
Meegan JE, Shaver CM, Putz ND, Jesse JJ, Landstreet SR, Lee HNR, Sidorova TN, McNeil JB, Wynn JL, Cheung-Flynn J, Komalavilas P, Brophy CM, Ware LB, Bastarache JA
(2020) PLoS One 15: e0228727
MeSH Terms: Animals, Apoptosis, Capillary Permeability, Endothelial Cells, Female, Hemoglobins, Humans, Inflammation, Lung, Mice, Mice, Inbred C57BL, Oxidative Stress, Sepsis
Show Abstract · Added March 3, 2020
Increased endothelial permeability is central to the pathogenesis of sepsis and leads to organ dysfunction and death but the endogenous mechanisms that drive increased endothelial permeability are not completely understood. We previously reported that cell-free hemoglobin (CFH), elevated in 80% of patients with sepsis, increases lung microvascular permeability in an ex vivo human lung model and cultured endothelial cells. In this study, we augmented a murine model of polymicrobial sepsis with elevated circulating CFH to test the hypothesis that CFH increases microvascular endothelial permeability by inducing endothelial apoptosis. Mice were treated with an intraperitoneal injection of cecal slurry with or without a single intravenous injection of CFH. Severity of illness, mortality, systemic and lung inflammation, endothelial injury and dysfunction and lung apoptosis were measured at selected time points. We found that CFH added to CS increased sepsis mortality, plasma inflammatory cytokines as well as lung apoptosis, edema and inflammation without affecting large vessel reactivity or vascular injury marker concentrations. These results suggest that CFH is an endogenous mediator of increased endothelial permeability and apoptosis in sepsis and may be a promising therapeutic target.
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13 MeSH Terms
Biased M receptor-positive allosteric modulators reveal role of phospholipase D in M-dependent rodent cortical plasticity.
Moran SP, Xiang Z, Doyle CA, Maksymetz J, Lv X, Faltin S, Fisher NM, Niswender CM, Rook JM, Lindsley CW, Conn PJ
(2019) Sci Signal 12:
MeSH Terms: Allosteric Site, Animals, CHO Cells, Calcium, Cerebral Cortex, Cognition, Cricetinae, Cricetulus, Electrophysiology, Female, Humans, Long-Term Synaptic Depression, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neuronal Plasticity, Phospholipase D, Prefrontal Cortex, Receptor, Muscarinic M1, Signal Transduction, Type C Phospholipases
Show Abstract · Added March 3, 2020
Highly selective, positive allosteric modulators (PAMs) of the M subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach to potentially improve cognitive function in patients suffering from Alzheimer's disease and schizophrenia. Discovery programs have produced a structurally diverse range of M receptor PAMs with distinct pharmacological properties, including different extents of agonist activity and differences in signal bias. This includes biased M receptor PAMs that can potentiate coupling of the receptor to activation of phospholipase C (PLC) but not phospholipase D (PLD). However, little is known about the role of PLD in M receptor signaling in native systems, and it is not clear whether biased M PAMs display differences in modulating M-mediated responses in native tissue. Using PLD inhibitors and PLD knockout mice, we showed that PLD was necessary for the induction of M-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Furthermore, biased M PAMs that did not couple to PLD not only failed to potentiate orthosteric agonist-induced LTD but also blocked M-dependent LTD in the PFC. In contrast, biased and nonbiased M PAMs acted similarly in potentiating M-dependent electrophysiological responses that were PLD independent. These findings demonstrate that PLD plays a critical role in the ability of M PAMs to modulate certain central nervous system (CNS) functions and that biased M PAMs function differently in brain regions implicated in cognition.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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2 Members
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22 MeSH Terms
Interpreting an apoptotic corpse as anti-inflammatory involves a chloride sensing pathway.
Perry JSA, Morioka S, Medina CB, Iker Etchegaray J, Barron B, Raymond MH, Lucas CD, Onengut-Gumuscu S, Delpire E, Ravichandran KS
(2019) Nat Cell Biol 21: 1532-1543
MeSH Terms: Animals, Apoptosis, Biological Transport, Cell Line, Cell Line, Tumor, Chlorides, Humans, Inflammation, Jurkat Cells, Mice, Mice, Inbred C57BL, Oxidative Stress, Phagocytes, Phagocytosis, Signal Transduction, Sodium-Potassium-Chloride Symporters, Transcription, Genetic
Show Abstract · Added March 18, 2020
Apoptotic cell clearance (efferocytosis) elicits an anti-inflammatory response by phagocytes, but the mechanisms that underlie this response are still being defined. Here, we uncover a chloride-sensing signalling pathway that controls both the phagocyte 'appetite' and its anti-inflammatory response. Efferocytosis transcriptionally altered the genes that encode the solute carrier (SLC) proteins SLC12A2 and SLC12A4. Interfering with SLC12A2 expression or function resulted in a significant increase in apoptotic corpse uptake per phagocyte, whereas the loss of SLC12A4 inhibited corpse uptake. In SLC12A2-deficient phagocytes, the canonical anti-inflammatory program was replaced by pro-inflammatory and oxidative-stress-associated gene programs. This 'switch' to pro-inflammatory sensing of apoptotic cells resulted from the disruption of the chloride-sensing pathway (and not due to corpse overload or poor degradation), including the chloride-sensing kinases WNK1, OSR1 and SPAK-which function upstream of SLC12A2-had a similar effect on efferocytosis. Collectively, the WNK1-OSR1-SPAK-SLC12A2/SLC12A4 chloride-sensing pathway and chloride flux in phagocytes are key modifiers of the manner in which phagocytes interpret the engulfed apoptotic corpse.
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MeSH Terms
Sox6 as a new modulator of renin expression in the kidney.
Saleem M, Hodgkinson CP, Xiao L, Gimenez-Bastida JA, Rasmussen ML, Foss J, Payne AJ, Mirotsou M, Gama V, Dzau VJ, Gomez JA
(2020) Am J Physiol Renal Physiol 318: F285-F297
MeSH Terms: Animals, Arterioles, Blood Pressure, Cell Differentiation, Cell Proliferation, Cells, Cultured, Diet, Sodium-Restricted, Diuretics, Furosemide, Gene Expression Regulation, Juxtaglomerular Apparatus, Male, Mesenchymal Stem Cells, Mice, Inbred C57BL, Mice, Knockout, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Renin, SOXD Transcription Factors, Signal Transduction
Show Abstract · Added August 24, 2020
Juxtaglomerular (JG) cells, major sources of renin, differentiate from metanephric mesenchymal cells that give rise to JG cells or a subset of smooth muscle cells of the renal afferent arteriole. During periods of dehydration and salt deprivation, renal mesenchymal stromal cells (MSCs) differentiate from JG cells. JG cells undergo expansion and smooth muscle cells redifferentiate to express renin along the afferent arteriole. Gene expression profiling comparing resident renal MSCs with JG cells indicates that the transcription factor Sox6 is highly expressed in JG cells in the adult kidney. In vitro, loss of Sox6 expression reduces differentiation of renal MSCs to renin-producing cells. In vivo, Sox6 expression is upregulated after a low-Na diet and furosemide. Importantly, knockout of Sox6 in Ren1d+ cells halts the increase in renin-expressing cells normally seen during a low-Na diet and furosemide as well as the typical increase in renin. Furthermore, Sox6 ablation in renin-expressing cells halts the recruitment of smooth muscle cells along the afferent arteriole, which normally express renin under these conditions. These results support a previously undefined role for Sox6 in renin expression.
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MeSH Terms