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Results: 1 to 10 of 79

Publication Record


Retrograde Degenerative Signaling Mediated by the p75 Neurotrophin Receptor Requires p150 Deacetylation by Axonal HDAC1.
Pathak A, Stanley EM, Hickman FE, Wallace N, Brewer B, Li D, Gluska S, Perlson E, Fuhrmann S, Akassoglou K, Bronfman F, Casaccia P, Burnette DT, Carter BD
(2018) Dev Cell 46: 376-387.e7
MeSH Terms: Animals, Axonal Transport, Axons, Dynactin Complex, Histone Deacetylase 1, Microtubule-Associated Proteins, Neurons, Rats, Sprague-Dawley, Receptor, Nerve Growth Factor
Show Abstract · Added March 27, 2019
During development, neurons undergo apoptosis if they do not receive adequate trophic support from tissues they innervate or when detrimental factors activate the p75 neurotrophin receptor (p75NTR) at their axon ends. Trophic factor deprivation (TFD) or activation of p75NTR in distal axons results in a retrograde degenerative signal. However, the nature of this signal and the regulation of its transport are poorly understood. Here, we identify p75NTR intracellular domain (ICD) and histone deacetylase 1 (HDAC1) as part of a retrograde pro-apoptotic signal generated in response to TFD or ligand binding to p75NTR in sympathetic neurons. We report an unconventional function of HDAC1 in retrograde transport of a degenerative signal and its constitutive presence in sympathetic axons. HDAC1 deacetylates dynactin subunit p150, which enhances its interaction with dynein. These findings define p75NTR ICD as a retrograde degenerative signal and reveal p150 deacetylation as a unique mechanism regulating axonal transport.
Copyright © 2018 Elsevier Inc. All rights reserved.
0 Communities
2 Members
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MeSH Terms
The C-terminal region of A-kinase anchor protein 350 (AKAP350A) enables formation of microtubule-nucleation centers and interacts with pericentriolar proteins.
Kolobova E, Roland JT, Lapierre LA, Williams JA, Mason TA, Goldenring JR
(2017) J Biol Chem 292: 20394-20409
MeSH Terms: A Kinase Anchor Proteins, Biomarkers, Cell Cycle Proteins, Cell Line, Centrosome, Cytoskeletal Proteins, Humans, Imaging, Three-Dimensional, Intracellular Signaling Peptides and Proteins, Luminescent Proteins, Microscopy, Electron, Transmission, Microtubule-Associated Proteins, Microtubule-Organizing Center, Models, Molecular, Nerve Tissue Proteins, Peptide Fragments, Phosphoproteins, Protein Interaction Domains and Motifs, Protein Interaction Mapping, Protein Multimerization, Proteomics, RNA Interference, Recombinant Fusion Proteins, Recombinant Proteins, Two-Hybrid System Techniques
Show Abstract · Added April 3, 2018
Microtubules in animal cells assemble (nucleate) from both the centrosome and the cis-Golgi cisternae. A-kinase anchor protein 350 kDa (AKAP350A, also called AKAP450/CG-NAP/AKAP9) is a large scaffolding protein located at both the centrosome and Golgi apparatus. Previous findings have suggested that AKAP350 is important for microtubule dynamics at both locations, but how this scaffolding protein assembles microtubule nucleation machinery is unclear. Here, we found that overexpression of the C-terminal third of AKAP350A, enhanced GFP-AKAP350A(2691-3907), induces the formation of multiple microtubule-nucleation centers (MTNCs). Nevertheless, these induced MTNCs lacked "true" centriole proteins, such as Cep135. Mapping analysis with AKAP350A truncations demonstrated that AKAP350A contains discrete regions responsible for promoting or inhibiting the formation of multiple MTNCs. Moreover, GFP-AKAP350A(2691-3907) recruited several pericentriolar proteins to MTNCs, including γ-tubulin, pericentrin, Cep68, Cep170, and Cdk5RAP2. Proteomic analysis indicated that Cdk5RAP2 and Cep170 both interact with the microtubule nucleation-promoting region of AKAP350A, whereas Cep68 interacts with the distal C-terminal AKAP350A region. Yeast two-hybrid assays established a direct interaction of Cep170 with AKAP350A. Super-resolution and deconvolution microscopy analyses were performed to define the association of AKAP350A with centrosomes, and these studies disclosed that AKAP350A spans the bridge between centrioles, co-localizing with rootletin and Cep68 in the linker region. siRNA-mediated depletion of AKAP350A caused displacement of both Cep68 and Cep170 from the centrosome. These results suggest that AKAP350A acts as a scaffold for factors involved in microtubule nucleation at the centrosome and coordinates the assembly of protein complexes associating with the intercentriolar bridge.
0 Communities
1 Members
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25 MeSH Terms
Microtubules regulate brush border formation.
Tonucci FM, Ferretti A, Almada E, Cribb P, Vena R, Hidalgo F, Favre C, Tyska MJ, Kaverina I, Larocca MC
(2018) J Cell Physiol 233: 1468-1480
MeSH Terms: Actin Cytoskeleton, Animals, Cell Polarity, Centromere, Colon, Dogs, Enterocytes, Epithelial Cells, Humans, Kidney, Madin Darby Canine Kidney Cells, Microtubule-Associated Proteins, Microtubules, Microvilli, Nocodazole, Time Factors, Tubulin Modulators
Show Abstract · Added April 10, 2018
Most epithelial cells contain apical membrane structures associated to bundles of actin filaments, which constitute the brush border. Whereas microtubule participation in the maintenance of the brush border identity has been characterized, their contribution to de novo microvilli organization remained elusive. Hereby, using a cell model of individual enterocyte polarization, we found that nocodazole induced microtubule depolymerization prevented the de novo brush border formation. Microtubule participation in brush border actin organization was confirmed in polarized kidney tubule MDCK cells. We also found that centrosome, but not Golgi derived microtubules, were essential for the initial stages of brush border development. During this process, microtubule plus ends acquired an early asymmetric orientation toward the apical membrane, which clearly differs from their predominant basal orientation in mature epithelia. In addition, overexpression of the microtubule plus ends associated protein CLIP170, which regulate actin nucleation in different cell contexts, facilitated brush border formation. In combination, the present results support the participation of centrosomal microtubule plus ends in the activation of the polarized actin organization associated to brush border formation, unveiling a novel mechanism of microtubule regulation of epithelial polarity.
© 2017 Wiley Periodicals, Inc.
0 Communities
1 Members
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MeSH Terms
Nuclear LC3 Associates with Slowly Diffusing Complexes that Survey the Nucleolus.
Kraft LJ, Manral P, Dowler J, Kenworthy AK
(2016) Traffic 17: 369-99
MeSH Terms: Active Transport, Cell Nucleus, Cell Nucleolus, HeLa Cells, Humans, Microtubule-Associated Proteins, Protein Binding, RNA, Ribosomal Proteins, Tubulin
Show Abstract · Added February 12, 2016
MAP1LC3B (microtubule-associated protein 1 light chain 3, LC3) is a key component of the autophagy pathway, contributing to both cargo selection and autophagosome formation in the cytoplasm. Emerging evidence suggests that nuclear forms of LC3 are also functionally important; however, the mechanisms that facilitate the nuclear targeting and trafficking of LC3 between the nucleus and cytoplasm under steady-state conditions are poorly understood. In this study, we examine how residues known to regulate the interactions between LC3 and other proteins or RNA (F52 L53, R68-R70 and G120) contribute to its nuclear targeting, nucleocytoplasmic transport and association with nucleoli and other nuclear components. We find that residues F52 L53 and R68-70, but not G120, regulate targeting of LC3 to the nucleus, its rates of nucleocytoplasmic transport and the apparent sizes of LC3-associated complexes in the nucleus inferred from fluorescence recovery after photobleaching (FRAP) measurements. We also show that LC3 is enriched in nucleoli and its triple arginine motif is especially important for nucleolar targeting. Finally, we identify a series of candidate nuclear LC3-interacting proteins using mass spectrometry, including MAP1B, tubulin and several 40S ribosomal proteins. These findings suggest LC3 is retained in the nucleus in association with high-molecular weight complexes that continuously scan the nucleolus.
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
0 Communities
1 Members
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9 MeSH Terms
KIM-1-/TIM-1-mediated phagocytosis links ATG5-/ULK1-dependent clearance of apoptotic cells to antigen presentation.
Brooks CR, Yeung MY, Brooks YS, Chen H, Ichimura T, Henderson JM, Bonventre JV
(2015) EMBO J 34: 2441-64
MeSH Terms: Antigen Presentation, Apoptosis, Autophagy-Related Protein 5, Autophagy-Related Protein-1 Homolog, CD4-Positive T-Lymphocytes, Cell Proliferation, HEK293 Cells, Hepatitis A Virus Cellular Receptor 1, Humans, Intracellular Signaling Peptides and Proteins, Lipoylation, Membrane Glycoproteins, Microtubule-Associated Proteins, Phagocytosis, Protein-Serine-Threonine Kinases, Reactive Oxygen Species, Receptors, Virus
Show Abstract · Added September 12, 2016
Phagocytosis of apoptotic cells by both professional and semi-professional phagocytes is required for resolution of organ damage and maintenance of immune tolerance. KIM-1/TIM-1 is a phosphatidylserine receptor that is expressed on epithelial cells and can transform the cells into phagocytes. Here, we demonstrate that KIM-1 phosphorylation and association with p85 results in encapsulation of phagosomes by lipidated LC3 in multi-membrane organelles. KIM-1-mediated phagocytosis is not associated with increased ROS production, and NOX inhibition does not block LC3 lipidation. Autophagy gene expression is required for efficient clearance of apoptotic cells and phagosome maturation. KIM-1-mediated phagocytosis leads to pro-tolerogenic antigen presentation, which suppresses CD4 T-cell proliferation and increases the percentage of regulatory T cells in an autophagy gene-dependent manner. Taken together, these data reveal a novel mechanism of epithelial biology linking phagocytosis, autophagy and antigen presentation to regulation of the inflammatory response.
© 2015 The Authors.
1 Communities
1 Members
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17 MeSH Terms
Targeting HCC Therapy: On or Off ToPiX?
Andl CD
(2015) Dig Dis Sci 60: 2219-21
MeSH Terms: Apoptosis, Carcinoma, Hepatocellular, Cell Cycle Proteins, Cell Proliferation, Epithelial-Mesenchymal Transition, Female, Humans, Liver Neoplasms, Male, Microtubule-Associated Proteins, Nuclear Proteins
Added October 13, 2015
0 Communities
1 Members
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11 MeSH Terms
A non-BRICHOS SFTPC mutant (SP-CI73T) linked to interstitial lung disease promotes a late block in macroautophagy disrupting cellular proteostasis and mitophagy.
Hawkins A, Guttentag SH, Deterding R, Funkhouser WK, Goralski JL, Chatterjee S, Mulugeta S, Beers MF
(2015) Am J Physiol Lung Cell Mol Physiol 308: L33-47
MeSH Terms: ATP-Binding Cassette Transporters, Adaptor Proteins, Signal Transducing, Amino Acid Substitution, Autophagy, Autophagy-Related Protein 8 Family, Female, Gene Expression Regulation, Genetic Diseases, Inborn, HEK293 Cells, Humans, Infant, Lung Diseases, Interstitial, Lysosomes, Membrane Potential, Mitochondrial, Microfilament Proteins, Microtubule-Associated Proteins, Mitochondria, Mutation, Missense, Proteostasis Deficiencies, Pulmonary Surfactant-Associated Protein C, Sequestosome-1 Protein, Ubiquitin-Protein Ligases, Vacuoles, rab GTP-Binding Proteins
Show Abstract · Added January 20, 2015
Mutation of threonine for isoleucine at codon 73 (I73T) in the human surfactant protein C (hSP-C) gene (SFTPC) accounts for a significant portion of SFTPC mutations associated with interstitial lung disease (ILD). Cell lines stably expressing tagged primary translation product of SP-C isoforms were generated to test the hypothesis that deposition of hSP-C(I73T) within the endosomal system promotes disruption of a key cellular quality control pathway, macroautophagy. By fluorescence microscopy, wild-type hSP-C (hSP-C(WT)) colocalized with exogenously expressed human ATP binding cassette class A3 (hABCA3), an indicator of normal trafficking to lysosomal-related organelles. In contrast, hSP-C(I73T) was dissociated from hABCA3 but colocalized to the plasma membrane as well as the endosomal network. Cells expressing hSP-C(I73T) exhibited increases in size and number of cytosolic green fluorescent protein/microtubule-associated protein 1 light-chain 3 (LC3) vesicles, some of which colabeled with red fluorescent protein from the gene dsRed/hSP-C(I73T). By transmission electron microscopy, hSP-C(I73T) cells contained abnormally large autophagic vacuoles containing organellar and proteinaceous debris, which phenocopied ultrastructural changes in alveolar type 2 cells in a lung biopsy from a SFTPC I73T patient. Biochemically, hSP-C(I73T) cells exhibited increased expression of Atg8/LC3, SQSTM1/p62, and Rab7, consistent with a distal block in autophagic vacuole maturation, confirmed by flux studies using bafilomycin A1 and rapamycin. Functionally, hSP-C(I73T) cells showed an impaired degradative capacity for an aggregation-prone huntingtin-1 reporter substrate. The disruption of autophagy-dependent proteostasis was accompanied by increases in mitochondria biomass and parkin expression coupled with a decrease in mitochondrial membrane potential. We conclude that hSP-C(I73T) induces an acquired block in macroautophagy-dependent proteostasis and mitophagy, which could contribute to the increased vulnerability of the lung epithelia to second-hit injury as seen in ILD.
Copyright © 2015 the American Physiological Society.
0 Communities
1 Members
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24 MeSH Terms
Dyskerin, tRNA genes, and condensin tether pericentric chromatin to the spindle axis in mitosis.
Snider CE, Stephens AD, Kirkland JG, Hamdani O, Kamakaka RT, Bloom K
(2014) J Cell Biol 207: 189-99
MeSH Terms: Adenosine Triphosphatases, Centrosome, Chromatin, DNA-Binding Proteins, Hydro-Lyases, Kinetochores, Microtubule-Associated Proteins, Mitosis, Multiprotein Complexes, RNA, Transfer, Ribonucleoproteins, Small Nuclear, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Spindle Apparatus
Show Abstract · Added January 25, 2016
Condensin is enriched in the pericentromere of budding yeast chromosomes where it is constrained to the spindle axis in metaphase. Pericentric condensin contributes to chromatin compaction, resistance to microtubule-based spindle forces, and spindle length and variance regulation. Condensin is clustered along the spindle axis in a heterogeneous fashion. We demonstrate that pericentric enrichment of condensin is mediated by interactions with transfer ribonucleic acid (tRNA) genes and their regulatory factors. This recruitment is important for generating axial tension on the pericentromere and coordinating movement between pericentromeres from different chromosomes. The interaction between condensin and tRNA genes in the pericentromere reveals a feature of yeast centromeres that has profound implications for the function and evolution of mitotic segregation mechanisms.
© 2014 Snider et al.
0 Communities
1 Members
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14 MeSH Terms
BDNF and Huntingtin protein modifications by manganese: implications for striatal medium spiny neuron pathology in manganese neurotoxicity.
Stansfield KH, Bichell TJ, Bowman AB, Guilarte TR
(2014) J Neurochem 131: 655-66
MeSH Terms: Animals, Brain, Brain-Derived Neurotrophic Factor, Cells, Cultured, Cerebral Cortex, Corpus Striatum, Dendritic Spines, Disease Models, Animal, Dose-Response Relationship, Drug, Embryo, Mammalian, Gene Expression Regulation, Huntingtin Protein, Manganese, Manganese Poisoning, Mice, Microtubule-Associated Proteins, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Phosphorylation, Rats, Rats, Sprague-Dawley
Show Abstract · Added February 15, 2016
High levels of manganese (Mn) exposure decrease striatal medium spiny neuron (MSN) dendritic length and spine density, but the mechanism(s) are not known. The Huntingtin (HTT) gene has been functionally linked to cortical brain-derived neurotrophic factor (BDNF) support of striatal MSNs via phosphorylation at serine 421. In Huntington's disease, pathogenic CAG repeat expansions of HTT decrease synthesis and disrupt transport of cortical-striatal BDNF, which may contribute to disease, and Mn is a putative environmental modifier of Huntington's disease pathology. Thus, we tested the hypothesis that changes in MSN dendritic morphology Mn due to exposure are associated with decreased BDNF levels and alterations in Htt protein. We report that BDNF levels are decreased in the striatum of Mn-exposed non-human primates and in the cerebral cortex and striatum of mice exposed to Mn. Furthermore, proBDNF and mature BDNF concentrations in primary cortical and hippocampal neuron cultures were decreased by exposure to Mn confirming the in vivo findings. Mn exposure decreased serine 421 phosphorylation of Htt in cortical and hippocampal neurons and increased total Htt levels. These data strongly support the hypothesis that Mn-exposure-related MSN pathology is associated with decreased BDNF trophic support via alterations in Htt.
© 2014 International Society for Neurochemistry.
0 Communities
1 Members
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22 MeSH Terms
Size, stoichiometry, and organization of soluble LC3-associated complexes.
Kraft LJ, Nguyen TA, Vogel SS, Kenworthy AK
(2014) Autophagy 10: 861-77
MeSH Terms: Autophagy, Cytoplasm, Fluorescence Recovery After Photobleaching, HEK293 Cells, HeLa Cells, Humans, Lipid Metabolism, Microtubule-Associated Proteins, Multiprotein Complexes, Phagosomes, Protein Binding, Protein Multimerization, Protein Processing, Post-Translational
Show Abstract · Added May 27, 2014
MAP1LC3B, an ortholog of yeast Atg8 and a member of the family of proteins formerly also known as ATG8 in mammals (LC3B henceforth in the text), functions in autophagosome formation and autophagy substrate recruitment. LC3 exists in both a soluble (autophagosome-independent) form as well as a lipid modified form that becomes tightly incorporated into autophagosomal membranes. Although LC3 is known to associate with tens of proteins, relatively little is known about soluble LC3 aside from its interactions with the LC3 lipid conjugation machinery. In previous studies we found autophagosome-independent GFP-LC3B diffuses unusually slowly for a protein of its size, suggesting it may constitutively associate with a high molecular weight complex, form homo-oligomers or aggregates, or reversibly bind microtubules or membranes. To distinguish between these possibilities, we characterized the size, stoichiometry, and organization of autophagosome-independent LC3B in living cells and in cytoplasmic extracts using fluorescence recovery after photobleaching (FRAP) and fluorescence polarization fluctuation analysis (FPFA). We found that the diffusion of LC3B was unaffected by either mutational disruption of its lipid modification or microtubule depolymerization. Brightness and homo-FRET analysis indicate LC3B does not homo-oligomerize. However, mutation of specific residues on LC3B required for binding other proteins and mRNA altered the effective hydrodynamic radius of the protein as well as its stoichiometry. We conclude that when not bound to autophagosomes, LC3B associates with a multicomponent complex with an effective size of ~500 kDa in the cytoplasm. These findings provide new insights into the nature of soluble LC3B and illustrate the power of FRAP and FPFA to investigate the emergent properties of protein complexes in the autophagy pathway.
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1 Members
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13 MeSH Terms