Dictyostelium Dynamin Superfamily GTPases Implicated in Vesicle Trafficking and Host-Pathogen Interactions

The haploid social amoeba Dictyostelium discoideum is a powerful model organism to study vesicle trafficking, motility and migration, cell division, developmental processes, and host cell-pathogen interactions. Dynamin superfamily proteins (DSPs) are large GTPases, which promote membrane fission and fusion, as well as membrane-independent cellular processes. Accordingly, DSPs play crucial roles for vesicle biogenesis and transport, organelle homeostasis, cytokinesis and cell-autonomous immunity. Major progress has been made over the last years in elucidating the function and structure of mammalian DSPs. D. discoideum produces at least eight DSPs, which are involved in membrane dynamics and other processes. The function and structure of these large GTPases has not been fully explored, despite the elaborate genetic and cell biological tools available for D. discoideum. In this review, we focus on the current knowledge about mammalian and D. discoideum DSPs, and we advocate the use of the genetically tractable amoeba to further study the role of DSPs in cell and infection biology. Particular emphasis is put on the virulence mechanisms of the facultative intracellular bacterium Legionella pneumophila.

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Structure and function of bacterial dynamin-like proteins

Biological Chemistry ◽

10.1515/hsz-2012-0185 ◽

2012 ◽

Vol 393 (11) ◽

pp. 1203-1214 ◽

Cited By ~ 41

Author(s):

Marc Bramkamp

Keyword(s):

Current Knowledge ◽

Structural Data ◽

Structure And Function ◽

Membrane Dynamics ◽

Gtp Hydrolysis ◽

Membrane Deformation ◽

Cellular Processes ◽

Structural And Functional Properties ◽

And Function ◽

Large Gtpases

Abstract Membrane dynamics are essential for numerous cellular processes in eukaryotic and prokaryotic cells. In eukaryotic cells, membrane fusion and fission are often catalyzed by large GTPases of the dynamin protein family. These proteins couple GTP hydrolysis to membrane deformation, which eventually leads to fusion or fission of the lipid bilayer. Mutations in eukaryotic dynamin-like proteins (DLPs) are associated with various diseases underscoring the importance to fully understand the biochemistry of these proteins. In recent years, a wealth of structural and biochemical data have been published that allow a detailed analysis of how dynamins or DLPs modulate biological membranes. However, less is known about the function of bacterial DLPs, although structural data exist. This review summarizes current knowledge about bacterial dynamins and discusses structural and functional properties in comparison to their eukaryotic counterparts.

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Creating a customized intracellular niche: subversion of host cell signaling byLegionellatype IV secretion system effectors

Canadian Journal of Microbiology ◽

10.1139/cjm-2015-0166 ◽

2015 ◽

Vol 61 (9) ◽

pp. 617-635 ◽

Cited By ~ 23

Author(s):

Ernest C. So ◽

Corinna Mattheis ◽

Edward W. Tate ◽

Gad Frankel ◽

Gunnar N. Schroeder

Keyword(s):

Host Cell ◽

Legionella Pneumophila ◽

Current Knowledge ◽

Secretion System ◽

Effector Proteins ◽

Cellular Processes ◽

Type Iv ◽

Open Questions ◽

Exact Function ◽

Wide Range

The Gram-negative facultative intracellular pathogen Legionella pneumophila infects a wide range of different protozoa in the environment and also human alveolar macrophages upon inhalation of contaminated aerosols. Inside its hosts, it creates a defined and unique compartment, termed the Legionella-containing vacuole (LCV), for survival and replication. To establish the LCV, L. pneumophila uses its Dot/Icm type IV secretion system (T4SS) to translocate more than 300 effector proteins into the host cell. Although it has become apparent in the past years that these effectors subvert a multitude of cellular processes and allow Legionella to take control of host cell vesicle trafficking, transcription, and translation, the exact function of the vast majority of effectors still remains unknown. This is partly due to high functional redundancy among the effectors, which renders conventional genetic approaches to elucidate their role ineffective. Here, we review the current knowledge about Legionella T4SS effectors, highlight open questions, and discuss new methods that promise to facilitate the characterization of T4SS effector functions in the future.

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Differential expression of DLG1 as a common trait in different human diseases: an encouraging issue in molecular pathology

Biological Chemistry ◽

10.1515/hsz-2018-0350 ◽

2019 ◽

Vol 400 (6) ◽

pp. 699-710 ◽

Cited By ~ 5

Author(s):

Federico Marziali ◽

María Paula Dizanzo ◽

Ana Laura Cavatorta ◽

Daniela Gardiol

Keyword(s):

Posttranslational Modifications ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Gene Mutations ◽

Scaffolding Protein ◽

Cellular Processes ◽

Cell Localization ◽

Open Questions ◽

Therapeutic Tools ◽

And Migration

AbstractHuman disc large (DLG1) is a scaffolding protein that through the interaction with diverse cell partners participates in the control of key cellular processes such as polarity, proliferation and migration. Experimental data have mainly identified DLG1 as a tumor suppressor. An outstanding point for DLG1 protein is that altered DLG1 expression andDLG1gene mutations were observed in different pathologies, including cancer and neurological and immunological disorders. Evident changes in DLG1 abundance and/or cell localization were identified in a number of studies suggesting its participation in molecular mechanisms responsible for the development of such illnesses. In this review, we focus on some of the latest findings regarding DLG1 alterations in different diseases as well as its potential use as a biomarker for pathological progression. We further address the current knowledge on the molecular mechanisms regulating DLG1 expression and the posttranslational modifications that may affect DLG1 cell localization and functions. Despite the advances in this field, there are still open questions about the precise molecular link between alterations in DLG1 expression and the development of each specific pathology. The complete understanding of this concern will give us new scenarios for the design of promising diagnosis and therapeutic tools.

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Molecular and Cellular Functions of the Linker Histone H1.2

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.773195 ◽

2022 ◽

Vol 9 ◽

Author(s):

Shuting Lai ◽

Jin Jia ◽

Xiaoyu Cao ◽

Ping-Kun Zhou ◽

Shanshan Gao

Keyword(s):

Genome Stability ◽

Target Genes ◽

Current Knowledge ◽

Linker Histone ◽

Cellular Functions ◽

Cancer Cell Growth ◽

Cell Growth And Migration ◽

Chromatin Dynamics ◽

Cellular Processes ◽

And Migration

Linker histone H1.2, which belongs to the linker histone family H1, plays a crucial role in the maintenance of the stable higher-order structures of chromatin and nucleosomes. As a critical part of chromatin structure, H1.2 has an important function in regulating chromatin dynamics and participates in multiple other cellular processes as well. Recent work has also shown that linker histone H1.2 regulates the transcription levels of certain target genes and affects different processes as well, such as cancer cell growth and migration, DNA duplication and DNA repair. The present work briefly summarizes the current knowledge of linker histone H1.2 modifications. Further, we also discuss the roles of linker histone H1.2 in the maintenance of genome stability, apoptosis, cell cycle regulation, and its association with disease.

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Multifunctional Roles of the Actin-Binding Protein Flightless I in Inflammation, Cancer and Wound Healing

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.603508 ◽

2020 ◽

Vol 8 ◽

Author(s):

Xanthe L. Strudwick ◽

Allison J. Cowin

Keyword(s):

Cancer Progression ◽

Wound Repair ◽

Actin Polymerization ◽

Hormone Receptors ◽

Current Knowledge ◽

Actin Binding ◽

Cellular Processes ◽

Physiological Processes ◽

Wide Range ◽

And Migration

Flightless I is an actin-binding member of the gelsolin family of actin-remodeling proteins that inhibits actin polymerization but does not possess actin severing ability. Flightless I functions as a regulator of many cellular processes including proliferation, differentiation, apoptosis, and migration all of which are important for many physiological processes including wound repair, cancer progression and inflammation. More than simply facilitating cytoskeletal rearrangements, Flightless I has other important roles in the regulation of gene transcription within the nucleus where it interacts with nuclear hormone receptors to modulate cellular activities. In conjunction with key binding partners Leucine rich repeat in the Flightless I interaction proteins (LRRFIP)1/2, Flightless I acts both synergistically and competitively to regulate a wide range of cellular signaling including interacting with two of the most important inflammatory pathways, the NLRP3 inflammasome and the MyD88-TLR4 pathways. In this review we outline the current knowledge about this important cytoskeletal protein and describe its many functions across a range of health conditions and pathologies. We provide perspectives for future development of Flightless I as a potential target for clinical translation and insights into potential therapeutic approaches to manipulate Flightless I functions.

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miR-125b enhances metastasis and progression of cancer via the TXNIP and HIF1α pathway in pancreatic cancer

Cancer Biomarkers ◽

10.3233/cbm-203112 ◽

2021 ◽

pp. 1-12

Author(s):

Pengli Wang ◽

Dan Zheng ◽

Hongyang Qi ◽

Qi Gao

Keyword(s):

Pancreatic Cancer ◽

Hypoxia Inducible Factor ◽

Immunofluorescence Assay ◽

Luciferase Assay ◽

Interacting Protein ◽

Over Expression ◽

Thioredoxin Interacting Protein ◽

Cellular Processes ◽

And Migration

BACKGROUND: MicroRNAs (miRNAs) play potential role in the development of various types of cancer conditions including pancreatic cancer (PC) targeting several cellular processes. Present study was aimed to evaluate function of miR-125b and the mechanism involved in PC. METHODS: Cell migration, MTT and BrdU study was done to establish the migration capability, cell viability and cell proliferation respectively. Binding sites for miR-125b were recognized by luciferase assay, expression of protein by western blot and immunofluorescence assay. In vivo study was done by BALB/c nude xenograft mice for evaluating the function of miR-125b. RESULTS: The study showed that expression of miR-125b was elevated in PC cells and tissues, and was correlated to proliferation and migration of cells. Also, over-expression of miR-125b encouraged migration, metastasis and proliferation of BxPC-3 cells, the suppression reversed it. We also noticed that thioredoxin-interacting protein (TXNIP) was the potential target of miR-125b. The outcomes also suggested that miR-125b governed the expression of TXNIP inversely via directly attaching to the 3′-UTR activating hypoxia-inducible factor 1α (HIF1α). Looking into the relation between HIF1α and TXNIP, we discovered that TXNIP caused the degradation and export of HIF1α by making a complex with it. CONCLUSION: The miR-125b-TXNIP-HIF1α pathway may serve useful strategy for diagnosing and treating PC.

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The Multiple Functions of Rho GTPases in Fission Yeasts

Cells ◽

10.3390/cells10061422 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1422

Author(s):

Jero Vicente-Soler ◽

Teresa Soto ◽

Alejandro Franco ◽

José Cansado ◽

Marisa Madrid

Keyword(s):

Fission Yeast ◽

Rho Gtpases ◽

Current Knowledge ◽

Model Organism ◽

Nucleotide Exchange ◽

Guanine Nucleotide Exchange ◽

Nucleotide Exchange Factors ◽

Physiological Processes ◽

Evolutionary Changes ◽

Rho Family

The Rho family of GTPases represents highly conserved molecular switches involved in a plethora of physiological processes. Fission yeast Schizosaccharomyces pombe has become a fundamental model organism to study the functions of Rho GTPases over the past few decades. In recent years, another fission yeast species, Schizosaccharomyces japonicus, has come into focus offering insight into evolutionary changes within the genus. Both fission yeasts contain only six Rho-type GTPases that are spatiotemporally controlled by multiple guanine–nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and whose intricate regulation in response to external cues is starting to be uncovered. In the present review, we will outline and discuss the current knowledge and recent advances on how the fission yeasts Rho family GTPases regulate essential physiological processes such as morphogenesis and polarity, cellular integrity, cytokinesis and cellular differentiation.

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Learning the distribution of single-cell chromosome conformations in bacteria reveals emergent order across genomic scales

Nature Communications ◽

10.1038/s41467-021-22189-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Joris J. B. Messelink ◽

Muriel C. F. van Teeseling ◽

Jacqueline Janssen ◽

Martin Thanbichler ◽

Chase P. Broedersz

Keyword(s):

Single Cell ◽

Caulobacter Crescentus ◽

Model Organism ◽

Super Resolution ◽

Chromosome Organization ◽

General Strategy ◽

Cell Axis ◽

Cellular Processes ◽

Emergent Order ◽

Genomic Clusters

AbstractThe order and variability of bacterial chromosome organization, contained within the distribution of chromosome conformations, are unclear. Here, we develop a fully data-driven maximum entropy approach to extract single-cell 3D chromosome conformations from Hi–C experiments on the model organism Caulobacter crescentus. The predictive power of our model is validated by independent experiments. We find that on large genomic scales, organizational features are predominantly present along the long cell axis: chromosomal loci exhibit striking long-ranged two-point axial correlations, indicating emergent order. This organization is associated with large genomic clusters we term Super Domains (SuDs), whose existence we support with super-resolution microscopy. On smaller genomic scales, our model reveals chromosome extensions that correlate with transcriptional and loop extrusion activity. Finally, we quantify the information contained in chromosome organization that may guide cellular processes. Our approach can be extended to other species, providing a general strategy to resolve variability in single-cell chromosomal organization.

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The Chinese Medicinal Formulation Guzhi Zengsheng Zhitongwan Modulates Chondrocyte Structure, Dynamics, and Metabolism by Controlling Multiple Functional Proteins

BioMed Research International ◽

10.1155/2018/9847286 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12

Author(s):

Baojin Yao ◽

Bocheng Lu ◽

Mei Zhang ◽

Hongwei Gao ◽

Xiangyang Leng ◽

...

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Research Field ◽

Medical Systems ◽

Cellular Processes ◽

Structure Dynamics ◽

National Medical ◽

Medicinal Formulation

Traditional Chinese medicine is one of the oldest medical systems in the world and has its unique principles and theories in the prevention and treatment of human diseases, which are achieved through the interactions of different types of materia medica in the form of Chinese medicinal formulations. GZZSZTW, a classical and effective Chinese medicinal formulation, was designed and created by professor Bailing Liu who is the only national medical master professor in the clinical research field of traditional Chinese medicine and skeletal diseases. GZZSZTW has been widely used in clinical settings for several decades for the treatment of joint diseases. However, the underlying molecular mechanisms are still largely unknown. In the present study, we performed quantitative proteomic analysis to investigate the effects of GZZSZTW on mouse primary chondrocytes using state-of-the-art iTRAQ technology. We demonstrated that the Chinese medicinal formulation GZZSZTW modulates chondrocyte structure, dynamics, and metabolism by controlling multiple functional proteins that are involved in the cellular processes of DNA replication and transcription, protein synthesis and degradation, cytoskeleton dynamics, and signal transduction. Thus, this study has expanded the current knowledge of the molecular mechanism of GZZSZTW treatment on chondrocytes. It has also shed new light on possible strategies to further prevent and treat cartilage-related diseases using traditional Chinese medicinal formulations.

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The role of hypoxia in endometrial cancer

Current Pharmaceutical Biotechnology ◽

10.2174/1389201022666210224130022 ◽

2021 ◽

Vol 22 ◽

Author(s):

Yarely M. Salinas-Vera ◽

Dolores Gallardo-Rincón ◽

Erika Ruíz-García ◽

Macrina B. Silva-Cázares ◽

Carmen Sol de la Peña-Cruz ◽

...

Keyword(s):

Endometrial Cancer ◽

Cell Survival ◽

Cancer Cells ◽

Cancer Cell ◽

Targeted Therapies ◽

Current Knowledge ◽

Vasculogenic Mimicry ◽

Cellular Processes ◽

Corpus Uteri

: Endometrial cancer represents the most frequent neoplasia from the corpus uteri, and comprises the 14th leading cause of death in women worldwide. Risk factors that contribute to the disease include early menarche, late menopause, nulliparity, and menopausal hormone use, as well as hypertension and obesity comorbidities. The clinical effectiveness of chemotherapy is variable, suggesting that novel molecular targeted therapies against specific cellular processes associated with the maintenance of cancer cell survival and therapy resistance urged to ameliorate the rates of success in endometrial cancer treatment. In the course of tumor growth, cancer cells must adapt to decreased oxygen availability in the microenvironment by upregulation of hypoxia-inducible factors, which orchestrate the activation of a transcriptional program leading to cell survival. During this adaptative process, the hypoxic cancer cells may acquire invasive and metastatic properties as well as increased cell proliferation and resistance to chemotherapy, enhanced angiogenesis, vasculogenic mimicry, and maintenance of cancer cell stemness, which contribute to more aggressive cancer phenotypes. Several studies have shown that hypoxia-inducible factor 1 alpha (HIF-1α) protein is aberrantly overexpressed in many solid tumors from breast, prostate, ovarian, bladder, colon, brain, and pancreas. Thus, it has been considered an important therapeutic target. Here, we reviewed the current knowledge of the relevant roles of cellular hypoxia mechanisms and HIF-1α functions in diverse processes associated with endometrial cancer progression. In addition, we also summarize the role of microRNAs in the posttranscriptional regulation of protein-encoding genes involved in the hypoxia response in endometrial cancer. Finally, we pointed out the need for urgent targeted therapies to impair the cellular processes activated by hypoxia in the tumor microenvironment.

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