scholarly journals Matrix stiffness controls ciliogenesis and centriole position

2021 ◽  
Author(s):  
Ivanna Williantarra ◽  
Sophia Leung ◽  
Yu Suk Choi ◽  
Ashika Chhana ◽  
Susan R McGlashan
Keyword(s):  
Primary Cilium ◽  
Cellular Response ◽  
Primary Cilia ◽  
Basal Membrane ◽  
Cell Types ◽  
Substrate Stiffness ◽  
Dependent Manner ◽  
Wide Range ◽  
The Matrix ◽  
External Forces

Mechanical stress and the stiffness of the extracellular matrix are key drivers of tissue development and homeostasis. Aberrant mechanosensation is associated with a wide range of pathologies, including diseases such as osteoarthritis. Substrate stiffness is one of the well-known mechanical properties of the matrix that enabled establishing the central dogma of an integrin-mediated mechanotransduction using stem cells. However, how specific cells 'feel' or sense substrate stiffness requires further study. The primary cilium is an essential cellular organelle that senses and integrates mechanical and chemical signals from the extracellular environment. We hypothesised that the primary cilium dynamically alters its length and position to fine-tune cell mechanosignalling based on substrate stiffness alone. We used a hydrogel system of varying substrate stiffness to examine the role of substrate stiffness on cilia frequency, length and centriole position as well as cell and nuclei area over time. Contrary to other cell types, we show that chondrocyte primary cilia shorten on softer substrates demonstrating tissue-specific mechanosensing which is aligned with the tissue stiffness the cells originate from. We further show that stiffness alone determine centriole positioning to either the basal or apical membranes during attachment and spreading, with centriole positioned towards the basal membrane on stiffer substrates. These phenomena are mediated by force generation actin-myosin stress fibres in a time-dependent manner. Based on these findings, we propose that substrate stiffness plays a central role in cilia positioning, regulating cellular response to external forces, and may be a key driver of mechanosignalling-associated diseases.

scholarly journals Interleukin-15 Activates Proinflammatory and Antimicrobial Functions in Polymorphonuclear Cells

1998 ◽  
Vol 66 (6) ◽  
pp. 2640-2647 ◽  
Author(s):  
Tiziana Musso ◽  
Liliana Calosso ◽  
Mario Zucca ◽  
Maura Millesimo ◽  
Manuela Puliti ◽  
...  
Keyword(s):  
Cellular Response ◽  
Cell Types ◽  
Polymorphonuclear Cells ◽  
Dependent Manner ◽  
Microbial Infection ◽  
Phagocytic Cells ◽  
Protein Levels ◽  
Reverse Transcription Pcr ◽  
Wide Range ◽  
Interleukin 15

ABSTRACT Interleukin-15 (IL-15) is a recently discovered cytokine produced by a wide range of different cell types including fibroblasts, keratinocytes, endothelial cells, and macrophages in response to lipopolysaccharide or microbial infection. This suggests that IL-15 may play a crucial role in the activation of phagocytic cells against pathogens. We studied polymorphonuclear leukocyte (PMN) activation by IL-15, evaluated as enhancement of PMN anti-Candidaactivity as well as IL-8 production, following stimulation with the cytokine. The PMN response to IL-15 depends on binding to the IL-15 receptor. Our experiments show that binding of a biotinylated human IL-15–immunoglobulin G2b IgG2b fusion protein was competed by the addition of human recombinant IL-15 (rIL-15) or of human rIL-2, suggesting that IL-15 binding to PMN might involve the IL-2Rβ and IL-2Rγ chains, which have been shown to be constitutively expressed by PMN. In addition, we show by reverse transcription-PCR and by flow cytometry with a specific anti-IL-15Rα chain monoclonal antibody that PMN express the IL-15Rα chain at the mRNA and protein levels. Incubation with IL-15 activated PMN to secrete the chemotactic factor IL-8, and the amount secreted was increased by costimulation with heat-inactivated Candida albicans. In addition, IL-15 primed the metabolic burst of PMN in response to formyl-methionyl-leucyl-phenylalanine but was not sufficient to trigger the respiratory burst or to increase the production of superoxide in PMN exposed to C. albicans. IL-15 also increased the ability of PMN to phagocytose heat-killed C. albicansorganisms in a dose-dependent manner, without opsonization by antibodies or complement-derived products. In the same concentration range, IL-15 was as effective as gamma interferon (IFN-γ) and IL-2 in increasing the C. albicans growth-inhibitory activity of PMN. Taken together, these results suggest that IL-15 is a potent stimulant of both proinflammatory and antifungal activities of PMN, activating several antimicrobial functions of PMN involved in the cellular response against C. albicans.

scholarly journals A New Story of the Three Magi: Scaffolding Proteins and lncRNA Suppressors of Cancer

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4264
Author(s):  
Larissa Kotelevets ◽  
Eric Chastre
Keyword(s):  
Tumor Suppressor ◽  
Intracellular Signaling ◽  
Cellular Response ◽  
Critical Role ◽  
Effector Proteins ◽  
Tumor Promoter ◽  
Hippo Signaling ◽  
Dependent Manner ◽  
Scaffolding Proteins ◽  
Wide Range

Scaffolding molecules exert a critical role in orchestrating cellular response through the spatiotemporal assembly of effector proteins as signalosomes. By increasing the efficiency and selectivity of intracellular signaling, these molecules can exert (anti/pro)oncogenic activities. As an archetype of scaffolding proteins with tumor suppressor property, the present review focuses on MAGI1, 2, and 3 (membrane-associated guanylate kinase inverted), a subgroup of the MAGUK protein family, that mediate networks involving receptors, junctional complexes, signaling molecules, and the cytoskeleton. MAGI1, 2, and 3 are comprised of 6 PDZ domains, 2 WW domains, and 1 GUK domain. These 9 protein binding modules allow selective interactions with a wide range of effectors, including the PTEN tumor suppressor, the β-catenin and YAP1 proto-oncogenes, and the regulation of the PI3K/AKT, the Wnt, and the Hippo signaling pathways. The frequent downmodulation of MAGIs in various human malignancies makes these scaffolding molecules and their ligands putative therapeutic targets. Interestingly, MAGI1 and MAGI2 genetic loci generate a series of long non-coding RNAs that act as a tumor promoter or suppressor in a tissue-dependent manner, by selectively sponging some miRNAs or by regulating epigenetic processes. Here, we discuss the different paths followed by the three MAGIs to control carcinogenesis.

Mechanotransductive Effects of Acoustic Radiation Force on Osteoblastic Primary Cilium, Cytoskeleton and Ca2+ Influx

2012 ◽  
Author(s):  
Y. X. Qin ◽  
S. Zhang ◽  
J. Cheng
Keyword(s):  
Primary Cilium ◽  
Bone Cells ◽  
Acoustic Radiation ◽  
Biological Effects ◽  
Radiation Force ◽  
Acoustic Radiation Force ◽  
Dependent Manner ◽  
Wide Range

Mechanotransduction has demonstrated potentials for tissue adaptation in vivo and in vitro. It is well documented that ultrasound, as a mechanical signal, can produce a wide variety of biological effects in vitro and in vivo[1]. For example, pulsed ultrasound can be used to accelerate the rate of bone fracture healing noninvasively. Although a wide range of studies have been done, mechanism for this therapeutic effect on bone healing is currently unknown and still under active investigation. In our previous studies, we have developed methodology allowed in vitro manipulating osteoblastic cells using acoustic radiation force (ARF) generated by ultrasound without the effects of acoustic streaming and ultrasound-induced temperature rise. Furthermore, we also confirmed that ARF modulated intracellular Ca2+ transient in MC3T3-E1 osteoblast-like cells in a strain and frequency-dependent manner. A potential mechanism by which bone cells may sense ultrasound is through their structures such as primary cilia and cytoskeletons. The purpose of the current study was to evaluate the hypothesis that acoustic radiation force can regulate the activities of the primary cilium and the cytoskeleton of the cells, which act as the mechanotransductive signals to mediate Ca2+ flux, as a pathway in response to cyclic loading.

scholarly journals The Roles of Primary Cilia in Cardiovascular Diseases

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 233 ◽  
Author(s):  
Rajasekharreddy Pala ◽  
Maha Jamal ◽  
Qamar Alshammari ◽  
Surya Nauli
Keyword(s):  
Cardiovascular Diseases ◽  
Primary Cilia ◽  
Cell Types ◽  
Molecular Defects ◽  
Flow Sensing ◽  
Intracellular Signals ◽  
Wide Range ◽  
No Signaling ◽  
Vascular Endothelia ◽  
And Function

Primary cilia are microtubule-based organelles found in most mammalian cell types. Cilia act as sensory organelles that transmit extracellular clues into intracellular signals for molecular and cellular responses. Biochemical and molecular defects in primary cilia are associated with a wide range of diseases, termed ciliopathies, with phenotypes ranging from polycystic kidney disease, liver disorders, mental retardation, and obesity to cardiovascular diseases. Primary cilia in vascular endothelia protrude into the lumen of blood vessels and function as molecular switches for calcium (Ca2+) and nitric oxide (NO) signaling. As mechanosensory organelles, endothelial cilia are involved in blood flow sensing. Dysfunction in endothelial cilia contributes to aberrant fluid-sensing and thus results in vascular disorders, including hypertension, aneurysm, and atherosclerosis. This review focuses on the most recent findings on the roles of endothelial primary cilia within vascular biology and alludes to the possibility of primary cilium as a therapeutic target for cardiovascular disorders.

scholarly journals Regulation of p53 and MDM2 Activity by MTBP

2005 ◽  
Vol 25 (2) ◽  
pp. 545-553 ◽  
Author(s):  
Mark Brady ◽  
Nikolina Vlatković ◽  
Mark T. Boyd
Keyword(s):  
Ubiquitin Ligase ◽  
Stress Responses ◽  
Nuclear Export ◽  
Cellular Response ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Dependent Manner ◽  
Γ Irradiation ◽  
Ubiquitin Ligase Activity ◽  
Wide Range

ABSTRACT p53 is a critical coordinator of a wide range of stress responses. To facilitate a rapid response to stress, p53 is produced constitutively but is negatively regulated by MDM2. MDM2 can inhibit p53 in multiple independent ways: by binding to its transcription activation domain, inhibiting p53 acetylation, promoting nuclear export, and probably most importantly by promoting proteasomal degradation of p53. The latter is achieved via MDM2's E3 ubiquitin ligase activity harbored within the MDM2 RING finger domain. We have discovered that MTBP promotes MDM2-mediated ubiquitination and degradation of p53 and also MDM2 stabilization in an MDM2 RING finger-dependent manner. Moreover, using small interfering RNA to down-regulate endogenous MTBP in unstressed cells, we have found that MTBP significantly contributes to MDM2-mediated regulation of p53 levels and activity. However, following exposure of cells to UV, but not γ-irradiation, MTBP is destabilized as part of the coordinated cellular response. Our findings suggest that MTBP differentially regulates the E3 ubiquitin ligase activity of MDM2 towards two of its most critical targets (itself and p53) and in doing so significantly contributes to MDM2-dependent p53 homeostasis in unstressed cells.

Molecular characterization and expression of the p38 MAPK gene from the ridgetail white prawn, Palaemon carinicauda Holthuis, 1950 (Decapoda, Palaemonidae)

Crustaceana ◽  
2017 ◽  
Vol 90 (11-12) ◽  
pp. 1427-1442
Author(s):  
Bei Xue ◽  
Pei Zhang ◽  
Zhi H. Li ◽  
Lian Zhao ◽  
Xiao F. Lai ◽  
...  
Keyword(s):  
Protein Kinases ◽  
P38 Mapk ◽  
Cellular Response ◽  
Distribution Patterns ◽  
Dependent Manner ◽  
Reading Frame ◽  
Close Phylogenetic Relationship ◽  
Wide Range ◽  
Mitogen Activated Protein ◽  
Extracellular Stimuli

The p38 mitogen-activated protein kinases (MAPK) are a kind of Ser/Thr protein kinases that convert extracellular stimuli into a wide range of cellular response, appearing to function not only in stress stimuli but also in development. To explore the function of p38 MAPK inPalaemon carinicaudaHolthuis, 1950, we cloned and characterized the full-length cDNA sequence (GenBank accession number KX893515) (designated asPc-p38). The results showed that the open reading frame (ORF) ofPc-p38was 1098 bp and it encoded a protein of 365 amino acids.Pc-p38contained the conserved structures of a Thr-Gly-Tyr (TGY) motif and a substrate-binding site, Ala-Thr-Arg-Trp (ATRW), and was shown to have a close phylogenetic relationship to other p38 MAPKs in crustaceans. The tissue distribution patterns showed thatPc-p38was widely expressed in all tissues, with highest expression in the hepatopancreas and ovary. Quantitative real-time PCR revealed thatPc-p38was upregulated during ecdysis, reaching a peak at 5 min post-moult, suggesting thatPc-p38may be involved in muscle remodeling after moulting. In addition, the expression ofPc-p38increased following exposure to different concentrations of mercury, in a dose- and time-dependent manner. In conclusion, anPc-p38gene was cloned and its role determined at different times post-moult and after stress from different concentrations of mercury, to further reveal the possible functions of p38 MAPK inP. carinicauda.

Pyrrolo-1,5-benzoxazepines: a new class of apoptotic agents

2001 ◽  
Vol 29 (6) ◽  
pp. 704-706 ◽  
Author(s):  
D. M. Zisterer ◽  
M. M. McGee ◽  
G. Campiani ◽  
A. Ramunno ◽  
C. Fattorusso ◽  
...  
Keyword(s):  
Cellular Response ◽  
Caspase 3 ◽  
Signal Transduction Pathway ◽  
Benzodiazepine Receptor ◽  
Cell Types ◽  
Dependent Manner ◽  
Apoptotic Pathway ◽  
Leukaemia Cell Line ◽  
Apoptotic Activity ◽  
Induced Apoptosis

Some members of a series of novel pyrrolo-1,5-benzoxazepines (PBOXs) potently induce apoptosis in a number of human cancerous cell lines including HL-60 cells and the drug-resistant chronic myelogenous leukaemia cell line, K562. The apoptotic induction seems to be independent of the mitochondrial peripheral-type benzodiazepine receptor (PBR), which binds these PBOXs with high affinity, due to a lack of correlation between their affinities for the receptor and their apoptotic potencies and their high apoptotic activity in PBR-deficient cells. PBOX-6, a potent member of the series, induces a transient activation of c-Jun N-terminal kinase (JNK) in a dose-dependent manner, which correlates with induction of apoptosis. Expression of a cytoplasmic inhibitor of the JNK signal transduction pathway, Jip-1, prevents JNK activity and significantly reduces the extent of apoptosis induced by PBOX-6. This demonstrates the requirement for JNK in the cellular response to this apoptotic agent. In addition, PBOX-6 activates caspase-3-like proteases in K562 and HL-60 cells. The caspase-3 inhibitor, Z-Asp-Glu-Val-Asp-fluoromethylketone (z-DEVD-fmk), blocks caspase-3-like protease activity in both cell types but only prevents PBOX-6-induced apoptosis in HL-60 cells, suggesting that the requirement for caspase-3-like proteases in the apoptotic pathway is dependent on the cell type.

scholarly journals An Autoantigen Profile from Jurkat T-Lymphoblasts Provides a Molecular Guide for Investigating Autoimmune Sequelae of COVID-19

2021 ◽  
Author(s):  
Julia Y. Wang ◽  
Wei Zhang ◽  
Michael W. Roehrl ◽  
Victor B. Roehrl ◽  
Michael H. Roehrl
Keyword(s):  
T Cells ◽  
Viral Infection ◽  
Cellular Response ◽  
Dermatan Sulfate ◽  
Wide Spectrum ◽  
Cell Types ◽  
Cytoskeletal Proteins ◽  
Wide Range ◽  
Shock Proteins ◽  
T Lymphoblasts

In order to understand autoimmune phenomena contributing to the pathophysiology of COVID-19 and post-COVID syndrome, we have been profiling autoantigens (autoAgs) from various cell types. Although cells share numerous autoAgs, each cell type gives rise to unique COVID-altered autoAg candidates, which may explain the wide range of symptoms experienced by patients with autoimmune sequelae of SARS-CoV-2 infection. Based on the unifying property of affinity between autoantigens (autoAgs) and the glycosaminoglycan dermatan sulfate (DS), this paper reports 140 candidate autoAgs identified from proteome extracts of human Jurkat T-cells, of which at least 105 (75%) are known targets of autoantibodies. Comparison with currently available multi-omic COVID-19 data shows that 125 (89%) of DS-affinity proteins are altered at protein and/or RNA levels in SARS-CoV-2-infected cells or patients, with at least 94 being known autoAgs in a wide spectrum of autoimmune diseases and cancer. Protein alterations by ubiquitination and phosphorylation in the viral infection are major contributors of autoAgs. The autoAg protein network is significantly associated with cellular response to stress, apoptosis, RNA metabolism, mRNA processing and translation, protein folding and processing, chromosome organization, cell cycle, and muscle contraction. The autoAgs include clusters of histones, CCT/TriC chaperonin, DNA replication licensing factors, proteasome and ribosome proteins, heat shock proteins, serine/arginine-rich splicing factors, 14-3-3 proteins, and cytoskeletal proteins. AutoAgs such as LCP1 and NACA that are altered in the T cells of COVID patients may provide insight into T-cell responses in the viral infection and merit further study. The autoantigen-ome from this study contributes to a comprehensive molecular map for investigating acute, subacute, and chronic autoimmune disorders caused by SARS-CoV-2.

scholarly journals Primary cilium remodeling mediates a cell signaling switch in differentiating neurons

2020 ◽  
Vol 6 (21) ◽  
pp. eabb0601 ◽  
Author(s):  
Gabriela Toro-Tapia ◽  
Raman M. Das
Keyword(s):  
High Resolution ◽  
Primary Cilium ◽  
Live Cell Imaging ◽  
Cellular Response ◽  
Cellular Differentiation ◽  
Cell Imaging ◽  
Cell Types ◽  
Morphological Variations ◽  
Axon Extension ◽  
A Cell

Cellular differentiation leads to the formation of specialized cell types and complex morphological variations. Often, differentiating cells transition between states by switching how they respond to the signaling environment. However, the mechanisms regulating these transitions are poorly understood. Differentiating neurons delaminate from the neuroepithelium through the regulated process of apical abscission, which mediates an acute loss of polarity and primary cilium disassembly. Using high-resolution live-cell imaging in chick neural tube, we show that these cells retain an Arl13b+ particle, which elongates and initiates intraflagellar trafficking as it transits toward the cell body, indicating primary cilium remodeling. Notably, disrupting cilia during and after remodeling inhibits axon extension and leads to axon collapse, respectively. Furthermore, cilium remodeling corresponds to a switch from a canonical to noncanonical cellular response to Shh. This work transforms our understanding of how cells can rapidly reinterpret signals to produce qualitatively different responses within the same tissue context.

scholarly journals Shuttling and sorting lipid-modified cargo into the cilia

2016 ◽  
Vol 44 (5) ◽  
pp. 1273-1280 ◽  
Author(s):  
Louise A. Stephen ◽  
Shehab Ismail
Keyword(s):  
Plasma Membrane ◽  
Human Cell ◽  
Primary Cilia ◽  
Cell Types ◽  
Dependent Manner ◽  
Membrane Composition ◽  
Small G Protein ◽  
Molecular Machinery ◽  
Modified Proteins ◽  
Almost All

Primary cilia are hair-like microtubule-based organelles that can be found on almost all human cell types. Although the cilium is not separated from the cell by membranes, their content is different from that of the cell body and their membrane composition is distinct from that of the plasma membrane. Here, we will introduce a molecular machinery that shuttles and sorts lipid-modified proteins to the cilium, thus contributing in maintaining its distinct composition. The mechanism involves the binding of the GDI-like solubilising factors, uncoordinated (UNC)119a, UNC119b and PDE6D, to the lipid-modified ciliary cargo and the specific release of the cargo in the cilia by the ciliary small G-protein Arl3 in a GTP-dependent manner.

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