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Start Over Author "A, BELL" Journal journal of biological chemistry
1,258 results on '"A, BELL"'

2. Inhibition of exchange proteins directly activated by cAMP as a strategy for broad-spectrum antiviral development

Author

Boulton, Stephen, Crupi, Mathieu J.F., Singh, Siddharth, Carter-Timofte, Madalina E., Azad, Taha, Organ, Bailey C., He, Xiaohong, Gill, Rida, Neault, Serge, Jamieson, Taylor, Dave, Jaahnavi, Kurmasheva, Naziia, Austin, Bradley, Petryk, Julia, Singaravelu, Ragunath, Huang, Ben Zhen, Franco, Noah, Babu, Kaaviya, Parks, Robin J., Ilkow, Carolina S., Olagnier, David, and Bell, John C.

Published
2023
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4. Moonlighting matrix metalloproteinase substrates: Enhancement of proinflammatory functions of extracellular tyrosyl-tRNA synthetase upon cleavage

Author

Jobin, Parker G, Solis, Nestor, Machado, Yoan, Bell, Peter A, Rai, Simran K, Kwon, Nam Hoon, Kim, Sunghoon, Overall, Christopher M, and Butler, Georgina S

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Chemokines, Chemotaxis, Enzyme Stability, Extracellular Space, Humans, Inflammation Mediators, Macrophages, Matrix Metalloproteinases, Models, Biological, Monocytes, NF-kappa B, Signal Transduction, Substrate Specificity, THP-1 Cells, Toll-Like Receptor 2, Tumor Necrosis Factor-alpha, Tyrosine, Tyrosine-tRNA Ligase, aminoacyl tRNA synthetase, inflammation, innate immunity, macrophage, matrix metalloproteinase, moonlighting proteins, multifunctional protein, proteolysis, toll-like receptor, Chemical Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences
Abstract

Tyrosyl-tRNA synthetase ligates tyrosine to its cognate tRNA in the cytoplasm, but it can also be secreted through a noncanonical pathway. We found that extracellular tyrosyl-tRNA synthetase (YRS) exhibited proinflammatory activities. In addition to acting as a monocyte/macrophage chemoattractant, YRS initiated signaling through Toll-like receptor 2 (TLR2) resulting in NF-κB activation and release of tumor necrosis factor α (TNFα) and multiple chemokines, including MIP-1α/β, CXCL8 (IL8), and CXCL1 (KC) from THP1 monocyte and peripheral blood mononuclear cell-derived macrophages. Furthermore, YRS up-regulated matrix metalloproteinase (MMP) activity in a TNFα-dependent manner in M0 macrophages. Because MMPs process a variety of intracellular proteins that also exhibit extracellular moonlighting functions, we profiled 10 MMPs for YRS cleavage and identified 55 cleavage sites by amino-terminal oriented mass spectrometry of substrates (ATOMS) positional proteomics and Edman degradation. Stable proteoforms resulted from cleavages near the start of the YRS C-terminal EMAPII domain. All of the MMPs tested cleaved at ADS386↓387LYV and VSG405↓406LVQ, generating 43- and 45-kDa fragments. The highest catalytic efficiency for YRS was demonstrated by MMP7, which is highly expressed by monocytes and macrophages, and by neutrophil-specific MMP8. MMP-cleaved YRS enhanced TLR2 signaling, increased TNFα secretion from macrophages, and amplified monocyte/macrophage chemotaxis compared with unprocessed YRS. The cleavage of YRS by MMP8, but not MMP7, was inhibited by tyrosine, a substrate of the YRS aminoacylation reaction. Overall, the proinflammatory activity of YRS is enhanced by MMP cleavage, which we suggest forms a feed-forward mechanism to promote inflammation.

Published
2020

5. Matrix metalloproteinases inactivate the proinflammatory functions of secreted moonlighting tryptophanyl-tRNA synthetase

Author

Jobin, Parker G, Solis, Nestor, Machado, Yoan, Bell, Peter A, Kwon, Nam Hoon, Kim, Sunghoon, Overall, Christopher M, and Butler, Georgina S

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Cells, Cultured, Endothelial Cells, Fibroblasts, Humans, Inflammation, Interferon-gamma, Macrophages, Matrix Metalloproteinases, Tryptophan-tRNA Ligase, multifunctional protein, aminoacyl tRNA synthetase, proteolysis, matrix metalloproteinase, interferon, inflammation, toll-like receptor, monocyte, macrophage, innate immunity, Chemical Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences
Abstract

Tryptophanyl-tRNA synthetase (WRS) is a cytosolic aminoacyl-tRNA synthetase essential for protein synthesis. WRS is also one of a growing number of intracellular proteins that are attributed distinct noncanonical "moonlighting" functions in the extracellular milieu. Moonlighting aminoacyl-tRNA synthetases regulate processes such as inflammation, but how these multifunctional enzymes are themselves regulated remains unclear. Here, we demonstrate that WRS is secreted from human macrophages, fibroblasts, and endothelial cells in response to the proinflammatory cytokine interferon γ (IFNγ). WRS signaled primarily through Toll-like receptor 2 (TLR2) in macrophages, leading to phosphorylation of the p65 subunit of NF-κB with associated loss of NF-κB inhibitor α (IκB-α) protein. This signaling initiated secretion of tumor necrosis factor α (TNFα) and CXCL8 (IL8) from macrophages. We also demonstrated that WRS is a potent monocyte chemoattractant. Of note, WRS increased matrix metalloproteinase (MMP) activity in the conditioned medium of macrophages in a TNFα-dependent manner. Using purified recombinant proteins and LC-MS/MS to identify proteolytic cleavage sites, we demonstrated that multiple MMPs, but primarily macrophage MMP7 and neutrophil MMP8, cleave secreted WRS at several sites. Loss of the WHEP domain following cleavage at Met48 generated a WRS proteoform that also results from alternative splicing, designated Δ1-47 WRS. The MMP-cleaved WRS lacked TLR signaling and proinflammatory activities. Thus, our results suggest that moonlighting WRS promotes IFNγ proinflammatory activities, and these responses can be dampened by MMPs.

Published
2019

18. Receptor Level Mechanisms Are Required for Epidermal Growth Factor (EGF)-stimulated Extracellular Signal-regulated Kinase (ERK) Activity Pulses*

Author

Sparta, Breanne, Pargett, Michael, Minguet, Marta, Distor, Kevin, Bell, George, and Albeck, John G

Subjects
Biochemistry and Cell Biology, Biological Sciences, Bioengineering, Underpinning research, 1.1 Normal biological development and functioning, Cell Line, Tumor, Enzyme Activation, Epidermal Growth Factor, Extracellular Signal-Regulated MAP Kinases, Humans, Kinetics, MAP Kinase Signaling System, Receptor, trkA, EKAR, ERKTR, TRK1-transforming tyrosine kinase protein, epidermal growth factor receptor, extracellular-signal-regulated kinase, fluorescence resonance energy transfer, mitogen-activated protein kinase, nerve growth factor, signal transduction, Chemical Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences
Abstract

In both physiological and cell culture systems, EGF-stimulated ERK activity occurs in discrete pulses within individual cells. Many feedback loops are present in the EGF receptor (EGFR)-ERK network, but the mechanisms driving pulsatile ERK kinetics are unknown. Here, we find that in cells that respond to EGF with frequency-modulated pulsatile ERK activity, stimulation through a heterologous TrkA receptor system results in non-pulsatile, amplitude-modulated activation of ERK. We further dissect the kinetics of pulse activity using a combination of FRET- and translocation-based reporters and find that EGFR activity is required to maintain ERK activity throughout the 10-20-minute lifetime of pulses. Together, these data indicate that feedbacks operating within the core Ras-Raf-MEK-ERK cascade are insufficient to drive discrete pulses of ERK activity and instead implicate mechanisms acting at the level of EGFR.

Published
2015

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