Post-translational modifications and stabilization of microtubules regulate transport of viral factors during infections

2021 ◽  
Vol 49 (4) ◽  
pp. 1735-1748
Author(s):  
Silvia Requena ◽  
Francisco Sánchez-Madrid ◽  
Noa B. Martín-Cófreces
Keyword(s):  
Immune Responses ◽  
Immune Cells ◽  
Building Blocks ◽  
Cell Types ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Associated Proteins ◽  
The Stability ◽  
Different Characteristics ◽  
Β Tubulin

Tubulin post-translational modifications (PTMs) constitute a source of diversity for microtubule (MT) functions, in addition to the different isotypes of α and β-tubulin acting as building blocks of MTs. Also, MT-associated proteins (MAPs) confer different characteristics to MTs. The combination of all these factors regulates the stability of these structures that act as rails to transport organelles within the cell, facilitating the association of motor complexes. All these functions are involved in crucial cellular processes in most cell types, ranging from spindle formation in mitosis to the defense against incoming cellular threats during phagocytosis mediated by immune cells. The regulation of MT dynamics through tubulin PTMs has evolved to depend on many different factors that act in a complex orchestrated manner. These tightly regulated processes are particularly relevant during the induction of effective immune responses against pathogens. Viruses have proved not only to hijack MTs and MAPs in order to favor an efficient infection, but also to induce certain PTMs that improve their cellular spread and lead to secondary consequences of viral processes. In this review, we offer a perspective on relevant MT-related elements exploited by viruses.

scholarly journals The inner junction complex of the cilia is an interaction hub that involves tubulin post-translational modifications

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ahmad Abdelzaher Zaki Khalifa ◽  
Muneyoshi Ichikawa ◽  
Daniel Dai ◽  
Shintaroh Kubo ◽  
Corbin Steven Black ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Tetrahymena Thermophila ◽  
Building Blocks ◽  
Post Translational Modifications ◽  
Ciliary Beating ◽  
Cryo Electron Microscopy ◽  
The Stability ◽  
And Function ◽  
Β Tubulin ◽  
Junction Proteins

Microtubules are cytoskeletal structures involved in stability, transport and organization in the cell. The building blocks, the α- and β-tubulin heterodimers, form protofilaments that associate laterally into the hollow microtubule. Microtubule also exists as highly stable doublet microtubules in the cilia where stability is needed for ciliary beating and function. The doublet microtubule maintains its stability through interactions at its inner and outer junctions where its A- and B-tubules meet. Here, using cryo-electron microscopy, bioinformatics and mass spectrometry of the doublets of Chlamydomonas reinhardtii and Tetrahymena thermophila, we identified two new inner junction proteins, FAP276 and FAP106, and an inner junction-associated protein, FAP126, thus presenting the complete answer to the inner junction identity and localization. Our structural study of the doublets shows that the inner junction serves as an interaction hub that involves tubulin post-translational modifications. These interactions contribute to the stability of the doublet and hence, normal ciliary motility.

scholarly journals The organisation and functions of local Ca2+ signals

2001 ◽  
Vol 114 (12) ◽  
pp. 2213-2222 ◽  
Author(s):  
Martin D. Bootman ◽  
Peter Lipp ◽  
Michael J. Berridge
Keyword(s):  
Cell Proliferation ◽  
Gene Transcription ◽  
Cell Biology ◽  
Building Blocks ◽  
Cell Types ◽  
Diverse Range ◽  
Cellular Processes ◽  
Different Cell Types ◽  
Intracellular Messenger ◽  
Sensory Mechanisms

Calcium (Ca2+) is a ubiquitous intracellular messenger, controlling a diverse range of cellular processes, such as gene transcription, muscle contraction and cell proliferation. The ability of a simple ion such as Ca2+ to play a pivotal role in cell biology results from the facility that cells have to shape Ca2+ signals in space, time and amplitude. To generate and interpret the variety of observed Ca2+ signals, different cell types employ components selected from a Ca2+ signalling ‘toolkit’, which comprises an array of homeostatic and sensory mechanisms. By mixing and matching components from the toolkit, cells can obtain Ca2+ signals that suit their physiology. Recent studies have demonstrated the importance of local Ca2+ signals in defining the specificity of the interaction of Ca2+ with its targets. Furthermore, local Ca2+ signals are the triggers and building blocks for larger global signals that propagate throughout cells.

Detyrosinated (Glu) microtubules are stabilized by an ATP-sensitive plus-end cap

2000 ◽  
Vol 113 (22) ◽  
pp. 3907-3919 ◽  
Author(s):  
A.S. Infante ◽  
M.S. Stein ◽  
Y. Zhai ◽  
G.G. Borisy ◽  
G.G. Gundersen
Keyword(s):  
Focal Adhesions ◽  
Cell Types ◽  
Cell Models ◽  
Microtubule Stability ◽  
Associated Proteins ◽  
Atp Breakdown ◽  
The Stability ◽  
Conventional Kinesin

Many cell types contain a subset of long-lived, ‘stable’ microtubules that differ from dynamic microtubules in that they are enriched in post-translationally detyrosinated tubulin (Glu-tubulin). Elevated Glu tubulin does not stabilize the microtubules and the mechanism for the stability of Glu microtubules is not known. We used detergent-extracted cell models to investigate the nature of Glu microtubule stability. In these cell models, Glu microtubules did not incorporate exogenously added tubulin subunits on their distal ends, while >70% of the bulk microtubules did. Ca(2+)-generated fragments of Glu microtubules incorporated tubulin, showing that Glu microtubule ends are capped. Consistent with this, Glu microtubules in cell models were resistant to dilution-induced breakdown. Known microtubule end-associated proteins (EB1, APC, p150(Glued) and vinculin focal adhesions) were not localized on Glu microtubule ends. ATP, but not nonhydrolyzable analogues, induced depolymerization of Glu microtubules in cell models. Timelapse and photobleaching studies showed that ATP triggered subunit loss from the plus end. ATP breakdown of Glu microtubules was inhibited by AMP-PNP and vanadate, but not by kinase or other inhibitors. Additional experiments showed that conventional kinesin or kif3 were not involved in Glu microtubule capping. We conclude that Glu microtubules are stabilized by a plus-end cap that includes an ATPase with properties similar to kinesins.

scholarly journals TAPping into the treasures of tubulin using novel protein production methods

2018 ◽  
Vol 62 (6) ◽  
pp. 781-792
Author(s):  
Nuo Yu ◽  
Niels Galjart
Keyword(s):  
Mammalian Cells ◽  
Gene Families ◽  
Cell Types ◽  
Cellular Functions ◽  
Tubulin Isotypes ◽  
Associated Proteins ◽  
Cytoskeletal Elements ◽  
Different Cell Types ◽  
Β Tubulin

Microtubules are cytoskeletal elements with important cellular functions, whose dynamic behaviour and properties are in part regulated by microtubule-associated proteins (MAPs). The building block of microtubules is tubulin, a heterodimer of α- and β-tubulin subunits. Longitudinal interactions between tubulin dimers facilitate a head-to-tail arrangement of dimers into protofilaments, while lateral interactions allow the formation of a hollow microtubule tube that mostly contains 13 protofilaments. Highly homologous α- and β-tubulin isotypes exist, which are encoded by multi-gene families. In vitro studies on microtubules and MAPs have largely relied on brain-derived tubulin preparations. However, these consist of an unknown mix of tubulin isotypes with undefined post-translational modifications. This has blocked studies on the functions of tubulin isotypes and the effects of tubulin mutations found in human neurological disorders. Fortunately, various methodologies to produce recombinant mammalian tubulins have become available in the last years, allowing researchers to overcome this barrier. In addition, affinity-based purification of tagged tubulins and identification of tubulin-associated proteins (TAPs) by mass spectrometry has revealed the ‘tubulome’ of mammalian cells. Future experiments with recombinant tubulins should allow a detailed description of how tubulin isotype influences basic microtubule behaviour, and how MAPs and TAPs impinge on tubulin isotypes and microtubule-based processes in different cell types.

scholarly journals Post-translational modifications of Hsp90 and translating the chaperone code

2020 ◽  
Vol 295 (32) ◽  
pp. 11099-11117 ◽  
Author(s):  
Sarah J. Backe ◽  
Rebecca A. Sager ◽  
Mark R. Woodford ◽  
Alan M. Makedon ◽  
Mehdi Mollapour
Keyword(s):  
Protein Complexes ◽  
Cell Cycle Control ◽  
Heat Shock Protein 90 ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Chaperone Function ◽  
Short Period ◽  
Evolutionarily Conserved ◽  
Hsp90 Chaperone ◽  
The Stability

Cells have a remarkable ability to synthesize large amounts of protein in a very short period of time. Under these conditions, many hydrophobic surfaces on proteins may be transiently exposed, and the likelihood of deleterious interactions is quite high. To counter this threat to cell viability, molecular chaperones have evolved to help nascent polypeptides fold correctly and multimeric protein complexes assemble productively, while minimizing the danger of protein aggregation. Heat shock protein 90 (Hsp90) is an evolutionarily conserved molecular chaperone that is involved in the stability and activation of at least 300 proteins, also known as clients, under normal cellular conditions. The Hsp90 clients participate in the full breadth of cellular processes, including cell growth and cell cycle control, signal transduction, DNA repair, transcription, and many others. Hsp90 chaperone function is coupled to its ability to bind and hydrolyze ATP, which is tightly regulated both by co-chaperone proteins and post-translational modifications (PTMs). Many reported PTMs of Hsp90 alter chaperone function and consequently affect myriad cellular processes. Here, we review the contributions of PTMs, such as phosphorylation, acetylation, SUMOylation, methylation, O-GlcNAcylation, ubiquitination, and others, toward regulation of Hsp90 function. We also discuss how the Hsp90 modification state affects cellular sensitivity to Hsp90-targeted therapeutics that specifically bind and inhibit its chaperone activity. The ultimate challenge is to decipher the comprehensive and combinatorial array of PTMs that modulate Hsp90 chaperone function, a phenomenon termed the “chaperone code.”

scholarly journals A single-cell atlas reveals shared and distinct immune responses and metabolism during SARS-CoV-2 and HIV-1 infections

2022 ◽  
Author(s):  
Tony Pan ◽  
Guoshuai Cao ◽  
Erting Tang ◽  
Yu Zhao ◽  
Pablo Penaloza-MacMaster ◽  
...  
Keyword(s):  
Immune Responses ◽  
Single Cell ◽  
Immune Cells ◽  
Viral Infections ◽  
Rho Gtpase ◽  
Cell Types ◽  
Disease Biology ◽  
Similarities And Differences ◽  
Different Cell Types ◽  
Hiv 1

SARS-CoV-2 and HIV-1 are RNA viruses that have killed millions of people worldwide. Understanding the similarities and differences between these two infections is critical for understanding disease progression and for developing effective vaccines and therapies, particularly for 38 million HIV-1+ individuals who are vulnerable to SARS-CoV-2 co-infection. Here, we utilized single-cell transcriptomics to perform a systematic comparison of 94,442 PBMCs from 7 COVID-19 and 9 HIV-1+ patients in an integrated immune atlas, in which 27 different cell types were identified using an accurate consensus single-cell annotation method. While immune cells in both cohorts show shared inflammation and disrupted mitochondrial function, COVID-19 patients exhibit stronger humoral immunity, broader IFN-I signaling, elevated Rho GTPase and mTOR pathway activities, and downregulated mitophagy. Our results elucidate transcriptional signatures associated with COVID-19 and HIV-1 that may reveal insights into fundamental disease biology and potential therapeutic targets to treat these viral infections.

scholarly journals Multi-Compartment 3D-Cultured Organ-on-a-Chip: Towards a Biomimetic Lymph Node for Drug Development

Pharmaceutics ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 464 ◽  
Author(s):  
Aya Shanti ◽  
Bisan Samara ◽  
Amal Abdullah ◽  
Nicholas Hallfors ◽  
Dino Accoto ◽  
...  
Keyword(s):  
Lymph Node ◽  
Drug Development ◽  
Immune Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Building Blocks ◽  
Cell Types ◽  
Matrix Composition ◽  
Encapsulated Cells

The interaction of immune cells with drugs and/or with other cell types should be mechanistically investigated in order to reduce attrition of new drug development. However, they are currently only limited technologies that address this need. In our work, we developed initial but significant building blocks that enable such immune-drug studies. We developed a novel microfluidic platform replicating the Lymph Node (LN) microenvironment called LN-on-a-chip, starting from design all the way to microfabrication, characterization and validation in terms of architectural features, fluidics, cytocompatibility, and usability. To prove the biomimetics of this microenvironment, we inserted different immune cell types in a microfluidic device, which showed an in-vivo-like spatial distribution. We demonstrated that the developed LN-on-a-chip incorporates key features of the native human LN, namely, (i) similarity in extracellular matrix composition, morphology, porosity, stiffness, and permeability, (ii) compartmentalization of immune cells within distinct structural domains, (iii) replication of the lymphatic fluid flow pattern, (iv) viability of encapsulated cells in collagen over the typical timeframe of immunotoxicity experiments, and (v) interaction among different cell types across chamber boundaries. Further studies with this platform may assess the immune cell function as a step forward to disclose the effects of pharmaceutics to downstream immunology in more physiologically relevant microenvironments.

scholarly journals Macrophages and the maintenance of homeostasis

2020 ◽  
Author(s):  
David M. Mosser ◽  
Kajal Hamidzadeh ◽  
Ricardo Goncalves
Keyword(s):  
Immune Responses ◽  
Immune Cells ◽  
Macrophage Polarization ◽  
The Body ◽  
Sensory Stimuli ◽  
Cellular Processes ◽  
Wide Range ◽  
Tissue Responses ◽  
Different Response

Abstract There have been many chapters written about macrophage polarization. These chapters generally focus on the role of macrophages in orchestrating immune responses by highlighting the T-cell-derived cytokines that shape these polarizing responses. This bias toward immunity is understandable, given the importance of macrophages to host defense. However, macrophages are ubiquitous and are involved in many different cellular processes, and describing them as immune cells is undoubtedly an oversimplification. It disregards their important roles in development, tissue remodeling, wound healing, angiogenesis, and metabolism, to name just a few processes. In this chapter, we propose that macrophages function as transducers in the body. According to Wikipedia, “A transducer is a device that converts energy from one form to another.” The word transducer is a term used to describe both the “sensor,” which can interpret a wide range of energy forms, and the “actuator,” which can switch voltages or currents to affect the environment. Macrophages are able to sense a seemingly endless variety of inputs from their environment and transduce these inputs into a variety of different response outcomes. Thus, rather than functioning as immune cells, they should be considered more broadly as cellular transducers that interpret microenvironmental changes and actuate vital tissue responses. In this chapter, we will describe some of the sensory stimuli that macrophages perceive and the responses they make to these stimuli to achieve their prime directive, which is the maintenance of homeostasis.

scholarly journals The Immunomodulatory Functions of Mesenchymal Stromal/Stem Cells Mediated via Paracrine Activity

2019 ◽  
Vol 8 (7) ◽  
pp. 1025 ◽  
Author(s):  
Yueyuan Zhou ◽  
Yusuke Yamamoto ◽  
Zhongdang Xiao ◽  
Takahiro Ochiya
Keyword(s):  
Stem Cells ◽  
Immune Responses ◽  
Immune Cells ◽  
Cell Types ◽  
Paracrine Signaling ◽  
Immune Microenvironment ◽  
Paracrine Factors ◽  
Diverse Range ◽  
Almost All ◽  
Stromal Stem Cells

Mesenchymal stromal/stem cells (MSCs) exist in almost all tissues, possessing the potential to differentiate into specialized cell types and exert immunomodulatory functions. Thus, they have attracted much attention as a promising therapeutic candidate. Recent studies have demonstrated that paracrine signaling is mainly responsible for the involvement of MSCs in the modulation of immune responses and the progression of diseases. Through release of secretome consisting of a diverse range of cytokines, chemokines, and extracellular vesicles (EVs), MSCs convey regulatory messages to recipient immune cells in the microenvironment. In this review, we focus on the recent advances in how MSCs contribute to immunomodulation through the secretion of paracrine factors. The further improved understanding of the molecular mechanism underlying the interactions between MSCs and immune cells highlights the paracrine biology of MSCs in the modulation of the immune microenvironment and promotes the clinical application of MSCs in regenerative medicine and immune diseases.

scholarly journals Distinct α- and β-tubulin isotypes are required for the positioning, differentiation and survival of neurons: new support for the ‘multi-tubulin’ hypothesis

2010 ◽  
Vol 30 (5) ◽  
pp. 319-330 ◽  
Author(s):  
Max A. Tischfield ◽  
Elizabeth C. Engle
Keyword(s):  
Nervous System ◽  
System Development ◽  
Nervous System Development ◽  
Cellular Functions ◽  
Microtubule Associated Proteins ◽  
Tubulin Isotypes ◽  
Cellular Processes ◽  
Associated Proteins ◽  
The Many ◽  
Β Tubulin

The many functions of the microtubule cytoskeleton are essential for shaping the development and maintaining the operation of the nervous system. With the recent discovery of congenital neurological disorders that result from mutations in genes that encode different α- and β-tubulin isotypes (TUBA1A, TUBB2B, TUBA8 and TUBB3), scientists have a novel paradigm to assess how select perturbations in microtubule function affect a range of cellular processes in humans. Moreover, important phenotypic distinctions found among the syndromes suggest that different tubulin isotypes can be utilized for distinct cellular functions during nervous system development. In the present review, we discuss: (i) the spectrum of congenital nervous system diseases that result from mutations in tubulin and MAPs (microtubule-associated proteins); (ii) the known or putative roles of these proteins during nervous system development; (iii) how the findings collectively support the ‘multi-tubulin’ hypothesis, which postulates that different tubulin isotypes may be required for specialized microtubule functions.

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