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Traffic (Copenhagen, Denmark) May 2016There is a fundamental gap in our understanding of how a eukaryotic cell apportions the limited space within its cell membrane. Upon infection, a cell competes with... (Review)
Review
There is a fundamental gap in our understanding of how a eukaryotic cell apportions the limited space within its cell membrane. Upon infection, a cell competes with intracellular pathogens for control of this same precious resource. The struggle between pathogen and host provides us with an opportunity to uncover the mechanisms regulating subcellular space by understanding how pathogens modulate vesicular traffic and membrane fusion events to create a specialized compartment for replication. By comparing several important intracellular pathogens, we review the molecular mechanisms and trafficking pathways that drive two space allocation strategies, the formation of tight and spacious pathogen-containing vacuoles. Additionally, we discuss the potential advantages of each pathogenic lifestyle, the broader implications these lifestyles might have for cellular biology and outline exciting opportunities for future investigation.
Topics: Host-Pathogen Interactions; Membrane Fusion; Vacuoles
PubMed: 26842840
DOI: 10.1111/tra.12382 -
FEBS Letters Nov 2016The genus Legionella belongs to Gram-negative bacteria found ubiquitously in aquatic habitats, where it grows in natural biofilms and replicates intracellularly in... (Review)
Review
The genus Legionella belongs to Gram-negative bacteria found ubiquitously in aquatic habitats, where it grows in natural biofilms and replicates intracellularly in various protozoa (amoebae, ciliates). L. pneumophila is known as the causative agent of Legionnaires' disease, since it is also able to replicate in human alveolar macrophages, finally leading to inflammation of the lung and pneumonia. To withstand the degradation by its host cells, a Legionella-containing vacuole (LCV) is established for intracellular replication, and numerous effector proteins are secreted into the host cytosol using a type four B secretion system (T4BSS). During intracellular replication, Legionella has a biphasic developmental cycle that alternates between a replicative and a transmissive form. New knowledge about the host-adapted and life stage-dependent metabolism of intracellular L. pneumophila revealed a bipartite metabolic network with life stage-specific usages of amino acids (e.g. serine), carbohydrates (e.g. glucose) and glycerol as major substrates. These metabolic features are associated with the differentiation of the intracellular bacteria, and thus have an important impact on the virulence of L. pneumophila.
Topics: Host-Parasite Interactions; Humans; Legionella pneumophila; Legionnaires' Disease; Metabolic Networks and Pathways; Type IV Secretion Systems; Vacuoles; Virulence
PubMed: 27455397
DOI: 10.1002/1873-3468.12326 -
Frontiers in Cellular and Infection... 2020Lysosomes are an integral part of the intracellular defense system against microbes. Lysosomal homeostasis in the host is adaptable and responds to conditions such as... (Review)
Review
Lysosomes are an integral part of the intracellular defense system against microbes. Lysosomal homeostasis in the host is adaptable and responds to conditions such as infection or nutritional deprivation. Pathogens such as () and avoid lysosomal targeting by actively manipulating the host vesicular trafficking and reside in a vacuole altered from the default lysosomal trafficking. In this review, the mechanisms by which the respective pathogen containing vacuoles (PCVs) intersect with lysosomal trafficking pathways and maintain their distinctness are discussed. Despite such active inhibition of lysosomal targeting, emerging literature shows that different pathogens or pathogen derived products exhibit a global influence on the host lysosomal system. Pathogen mediated lysosomal enrichment promotes the trafficking of a sub-set of pathogens to lysosomes, indicating heterogeneity in the host-pathogen encounter. This review integrates recent advancements on the global lysosomal alterations upon infections and the host protective role of the lysosomes against these pathogens. The review also briefly discusses the heterogeneity in the lysosomal targeting of these pathogens and the possible mechanisms and consequences.
Topics: Host-Pathogen Interactions; Lysosomes; Mycobacterium tuberculosis; Vacuoles
PubMed: 33330138
DOI: 10.3389/fcimb.2020.595502 -
The New Phytologist Apr 2020Vacuolar processing enzyme (VPE) is a cysteine-type endopeptidase that has a substrate-specificity for asparagine or aspartic acid residues and cleaves peptide bonds at... (Review)
Review
Vacuolar processing enzyme (VPE) is a cysteine-type endopeptidase that has a substrate-specificity for asparagine or aspartic acid residues and cleaves peptide bonds at their carboxyl-terminal side. Various vacuolar proteins are synthesized as larger proprotein precursors, and VPE is an important initiator of maturation and activation of these proteins. It mediates programmed cell death (PCD) by provoking vacuolar rupture and initiating the proteolytic cascade leading to PCD. Vacuolar processing enzyme also possesses a peptide ligation activity, which is responsible for producing cyclic peptides in several plant species. These unique functions of VPE support developmental and environmental responses in plants. The number of VPE homologues is higher in angiosperm species, indicating that there has been differentiation and specialization of VPE function over the course of evolution. Angiosperm VPEs are separated into two major types: the γ-type VPEs, which are expressed mainly in vegetative organs, and the β-type VPEs, whose expression occurs mainly in storage organs; in eudicots, the δ-type VPEs are further separated within γ-type VPEs. This review also considers the importance of processing and peptide ligation by VPE in vacuolar protein maturation.
Topics: Animals; Cysteine Endopeptidases; Life Cycle Stages; Plant Proteins; Plants; Vacuoles
PubMed: 31679161
DOI: 10.1111/nph.16306 -
The Journal of Cell Biology Oct 2019Protein folding is inherently error prone, especially in the endoplasmic reticulum (ER). Even with an elaborate network of molecular chaperones and protein folding... (Review)
Review
Protein folding is inherently error prone, especially in the endoplasmic reticulum (ER). Even with an elaborate network of molecular chaperones and protein folding facilitators, misfolding can occur quite frequently. To maintain protein homeostasis, eukaryotes have evolved a series of protein quality-control checkpoints. When secretory pathway quality-control pathways fail, stress response pathways, such as the unfolded protein response (UPR), are induced. In addition, the ER, which is the initial hub of protein biogenesis in the secretory pathway, triages misfolded proteins by delivering substrates to the proteasome or to the lysosome/vacuole through ER-associated degradation (ERAD) or ER-phagy. Some misfolded proteins escape the ER and are instead selected for Golgi quality control. These substrates are targeted for degradation after retrieval to the ER or delivery to the lysosome/vacuole. Here, we discuss how these guardian pathways function, how their activities intersect upon induction of the UPR, and how decisions are made to dispose of misfolded proteins in the secretory pathway.
Topics: Animals; Endoplasmic Reticulum; Humans; Lysosomes; Proteins; Secretory Pathway; Vacuoles
PubMed: 31537714
DOI: 10.1083/jcb.201906047 -
PLoS Pathogens Jul 2023L. pneumophila propagates in eukaryotic cells within a specialized niche, the Legionella-containing vacuole (LCV). The infection process is controlled by over 330...
L. pneumophila propagates in eukaryotic cells within a specialized niche, the Legionella-containing vacuole (LCV). The infection process is controlled by over 330 effector proteins delivered through the type IV secretion system. In this study, we report that the Legionella MavH effector localizes to endosomes and remodels host actin cytoskeleton in a phosphatidylinositol 3-phosphate (PI(3)P) dependent manner when ectopically expressed. We show that MavH recruits host actin capping protein (CP) and actin to the endosome via its CP-interacting (CPI) motif and WH2-like actin-binding domain, respectively. In vitro assays revealed that MavH stimulates actin assembly on PI(3)P-containing liposomes causing their tubulation. In addition, the recruitment of CP by MavH negatively regulates F-actin density at the membrane. We further show that, in L. pneumophila-infected cells, MavH appears around the LCV at the very early stage of infection and facilitates bacterium entry into the host. Together, our results reveal a novel mechanism of membrane tubulation induced by membrane-dependent actin polymerization catalyzed by MavH that contributes to the early stage of L. pneumophila infection by regulating host actin dynamics.
Topics: Legionella pneumophila; Actins; Polymerization; Phosphatidylinositol Phosphates; Vacuoles; Bacterial Proteins
PubMed: 37463171
DOI: 10.1371/journal.ppat.1011512 -
Frontiers in Cellular and Infection... 2018Environmental bacteria of the genus naturally parasitize free-living amoebae. Upon inhalation of bacteria-laden aerosols, the opportunistic pathogens grow... (Review)
Review
Environmental bacteria of the genus naturally parasitize free-living amoebae. Upon inhalation of bacteria-laden aerosols, the opportunistic pathogens grow intracellularly in alveolar macrophages and can cause a life-threatening pneumonia termed Legionnaires' disease. Intracellular replication in amoebae and macrophages takes place in a unique membrane-bound compartment, the -containing vacuole (LCV). LCV formation requires the bacterial Icm/Dot type IV secretion system, which translocates literally hundreds of "effector" proteins into host cells, where they modulate crucial cellular processes for the pathogen's benefit. The mechanism of LCV formation appears to be evolutionarily conserved, and therefore, amoebae are not only ecologically significant niches for spp., but also useful cellular models for eukaryotic phagocytes. In particular, and emerged over the last years as versatile and powerful models. Using genetic, biochemical and cell biological approaches, molecular interactions between amoebae and have recently been investigated in detail with a focus on the role of phosphoinositide lipids, small and large GTPases, autophagy components and the retromer complex, as well as on bacterial effectors targeting these host factors.
Topics: Acanthamoeba; Acanthamoeba castellanii; Amoeba; Animals; Autophagy; Bacterial Proteins; Dictyostelium; Disease Models, Animal; Drug Evaluation, Preclinical; Evolution, Molecular; GTP Phosphohydrolases; Host-Pathogen Interactions; Legionella; Legionella pneumophila; Legionnaires' Disease; Macrophages; Phosphatidylinositols; Proteomics; Type IV Secretion Systems; Vacuoles
PubMed: 29552544
DOI: 10.3389/fcimb.2018.00061 -
Frontiers in Cellular and Infection... 2015Certain pathogenic bacteria adopt an intracellular lifestyle and proliferate in eukaryotic host cells. The intracellular niche protects the bacteria from cellular and... (Review)
Review
Certain pathogenic bacteria adopt an intracellular lifestyle and proliferate in eukaryotic host cells. The intracellular niche protects the bacteria from cellular and humoral components of the mammalian immune system, and at the same time, allows the bacteria to gain access to otherwise restricted nutrient sources. Yet, intracellular protection and access to nutrients comes with a price, i.e., the bacteria need to overcome cell-autonomous defense mechanisms, such as the bactericidal endocytic pathway. While a few bacteria rupture the early phagosome and escape into the host cytoplasm, most intracellular pathogens form a distinct, degradation-resistant and replication-permissive membranous compartment. Intracellular bacteria that form unique pathogen vacuoles include Legionella, Mycobacterium, Chlamydia, Simkania, and Salmonella species. In order to understand the formation of these pathogen niches on a global scale and in a comprehensive and quantitative manner, an inventory of compartment-associated host factors is required. To this end, the intact pathogen compartments need to be isolated, purified and biochemically characterized. Here, we review recent progress on the isolation and purification of pathogen-modified vacuoles and membranes, as well as their proteomic characterization by mass spectrometry and different validation approaches. These studies provide the basis for further investigations on the specific mechanisms of pathogen-driven compartment formation.
Topics: Bacterial Physiological Phenomena; Host-Pathogen Interactions; Humans; Intracellular Membranes; Mass Spectrometry; Proteome; Proteomics; Vacuoles
PubMed: 26082896
DOI: 10.3389/fcimb.2015.00048 -
The New Phytologist Feb 2020Active removal of Na from the cytosol into the vacuole plays a critical role in salinity tissue tolerance, but another, often neglected component of this trait is Na... (Review)
Review
Active removal of Na from the cytosol into the vacuole plays a critical role in salinity tissue tolerance, but another, often neglected component of this trait is Na retention in vacuoles. This retention is based on an efficient control of Na -permeable slow- and fast-vacuolar channels that mediate the back-leak of Na into cytosol and, if not regulated tightly, could result in a futile cycle. This Tansley insight summarizes our current knowledge of regulation of tonoplast Na -permeable channels and discusses the energy cost of vacuolar Na sequestration, under different scenarios. We also report on a phylogenetic and bioinformatic analysis of the plant two-pore channel family and the difference in its structure and regulation between halophytes and glycophytes, in the context of salinity tolerance.
Topics: Energy Metabolism; Plant Proteins; Proton Pumps; Salt-Tolerant Plants; Sodium; Vacuoles
PubMed: 30802968
DOI: 10.1111/nph.15758 -
Trends in Biochemical Sciences Jun 2019In eukaryotes, organelles and vesicles modulate their contents and identities through highly regulated membrane fusion events. Membrane trafficking and fusion are... (Review)
Review
In eukaryotes, organelles and vesicles modulate their contents and identities through highly regulated membrane fusion events. Membrane trafficking and fusion are carried out through a series of stages that lead to the formation of SNARE complexes between cellular compartment membranes to trigger fusion. Although the protein catalysts of membrane fusion are well characterized, their response to their surrounding microenvironment, provided by the lipid composition of the membrane, remains to be fully understood. Membranes are composed of bulk lipids (e.g., phosphatidylcholine), as well as regulatory lipids that undergo constant modifications by kinases, phosphatases, and lipases. These lipids include phosphoinositides, diacylglycerol, phosphatidic acid, and cholesterol/ergosterol. Here we describe the roles of these lipids throughout the stages of yeast vacuole homotypic fusion.
Topics: Cholesterol; Ergosterol; Glycerides; Humans; Membrane Fusion; Phosphatidic Acids; Phosphatidylinositols; Vacuoles
PubMed: 30587414
DOI: 10.1016/j.tibs.2018.12.003