-
Autophagy May 2017Macroautophagy/autophagy is a membrane trafficking and intracellular degradation process involving the formation of double-membrane autophagosomes and their ultimate... (Review)
Review
Macroautophagy/autophagy is a membrane trafficking and intracellular degradation process involving the formation of double-membrane autophagosomes and their ultimate fusion with lysosomes. Much is yet to be learned about the regulation of this process, especially at the level of the membranes and lipids involved. We have recently found that the PX domain protein HS1BP3 (HCLS1 binding protein 3) is a negative regulator of autophagosome formation. HS1BP3 depletion increases the formation of LC3-positive autophagosomes both in human cells and zebrafish. HS1BP3 localizes to ATG16L1- and ATG9-positive autophagosome precursors deriving from recycling endosomes, which appear to fuse with LC3-positive phagophores. The HS1BP3 PX domain interacts with phosphatidic acid (PA) and 3'-phosphorylated phosphoinositides. When HS1BP3 is depleted, the total cellular PA content is upregulated stemming from increased activity of the PA-producing enzyme PLD (phospholipase D) and increased localization of PLD1 to ATG16L1-positive membranes. We propose that HS1BP3 negatively regulates autophagy by decreasing the PA content of the ATG16L1-positive autophagosome precursor membranes through inhibition of PLD1 activity and localization.
Topics: Animals; Autophagy; Autophagy-Related Proteins; Endosomes; Humans; Nerve Tissue Proteins; Phagosomes; Phospholipase D
PubMed: 28318354
DOI: 10.1080/15548627.2017.1291483 -
Microbiology Spectrum Jun 2016Phagocytosis refers to the active process that allows cells to take up large particulate material upon binding to surface receptors. The discovery of phagocytosis in... (Review)
Review
Phagocytosis refers to the active process that allows cells to take up large particulate material upon binding to surface receptors. The discovery of phagocytosis in 1883 by Elie Metchnikoff, leading to the concept that specialized cells are implicated in the defense against microbes, was one of the starting points of the field of immunology. After more than a century of research, phagocytosis is now appreciated to be a widely used process that enables the cellular uptake of a remarkable variety of particles, including bacteria, fungi, parasites, viruses, dead cells, and assorted debris and solid materials. Uptake of foreign particles is performed almost exclusively by specialized myeloid cells, commonly termed "professional phagocytes": neutrophils, monocytes, macrophages, and dendritic cells. Phagocytosis of microbes not only stops or at least restricts the spread of infection but also plays an important role in regulating the innate and adaptive immune responses. Activation of the myeloid cells upon phagocytosis leads to the secretion of cytokines and chemokines that convey signals to a variety of immune cells. Moreover, foreign antigens generated by the degradation of microbes following phagocytosis are loaded onto the major histocompatibility complex for presentation to specific T lymphocytes. However, phagocytosis is not restricted to professional myeloid phagocytes; an expanding diversity of cell types appear capable of engulfing apoptotic bodies and debris, playing a critical role in tissue remodeling and in the clearance of billions of effete cells every day.
Topics: Animals; Humans; Organelle Biogenesis; Phagocytes; Phagocytosis; Phagosomes
PubMed: 27337463
DOI: 10.1128/microbiolspec.MCHD-0013-2015 -
Frontiers in Bioscience (Landmark... Jun 2017Lipids are one of the major subcellular constituents and serve as signal molecules, energy sources, metabolic precursors and structural membrane components in various... (Review)
Review
Lipids are one of the major subcellular constituents and serve as signal molecules, energy sources, metabolic precursors and structural membrane components in various organisms. The function of lipids can be modified by multiple biochemical processes such as (de-)phosphorylation or (de-)glycosylation, and the organization of fatty acids into distinct cellular pools and subcellular compartments plays a pivotal role for the morphology and function of various cell populations. Thus, lipids regulate, for example, phagosome formation and maturation within host cells and thus, are critical for the elimination of microbial pathogens. Vice versa, microbial pathogens can manipulate the lipid composition of phagosomal membranes in host cells, and thus avoid their delivery to phagolysosomes. Lipids of microbial origin belong also to the strongest and most versatile inducers of mammalian immune responses upon engagement of distinct receptors on myeloid and lymphoid cells. Furthermore, microbial lipid toxins can induce membrane injuries and cell death. Thus, we will review here selected examples for mutual host-microbe interactions within the broad and divergent universe of lipids in microbial defense, tissue injury and immune evasion.
Topics: Animals; Autophagy; Bacteria; Fungi; Host-Pathogen Interactions; Humans; Lipid Metabolism; Lipids; Phagosomes; Signal Transduction
PubMed: 28410133
DOI: 10.2741/4559 -
Cellular and Molecular Life Sciences :... Mar 2018Autophagy is a highly regulated process in eukaryotes to maintain homeostasis and manage stress responses. Understanding the regulatory mechanisms and key players... (Review)
Review
Autophagy is a highly regulated process in eukaryotes to maintain homeostasis and manage stress responses. Understanding the regulatory mechanisms and key players involved in autophagy will provide critical insights into disease-related pathogenesis and potential clinical treatments. In this review, we describe the hallmark events involved in autophagy, from its initiation, to the final destruction of engulfed targets. Furthermore, based on structural and biochemical data, we evaluate the roles of key players in these processes and provide rationale as to how they control autophagic events in a highly ordered manner.
Topics: Animals; Autophagy; Humans; Lysosomes; Membrane Fusion; Models, Biological; Phagosomes; Protein Binding
PubMed: 28939950
DOI: 10.1007/s00018-017-2657-z -
Cellular Microbiology Aug 2014Human neutrophils represent the predominant leucocyte in circulation and the first responder to infection. Concurrent with ingestion of microorganisms, neutrophils... (Review)
Review
Human neutrophils represent the predominant leucocyte in circulation and the first responder to infection. Concurrent with ingestion of microorganisms, neutrophils activate and assemble the NADPH oxidase at the phagosome, thereby generating superoxide anion and hydrogen peroxide. Concomitantly, granules release their contents into the phagosome, where the antimicrobial proteins and enzymes synergize with oxidants to create an environment toxic to the captured microbe. The most rapid and complete antimicrobial action by human neutrophils against many organisms relies on the combined efforts of the azurophilic granule protein myeloperoxidase and hydrogen peroxide from the NADPH oxidase to oxidize chloride, thereby generating hypochlorous acid and a host of downstream reaction products. Although individual components of the neutrophil antimicrobial response exhibit specific activities in isolation, the situation in the environment of the phagosome is far more complicated, a consequence of multiple and complex interactions among oxidants, proteins and their by-products. In most cases, the cooperative interactions among the phagosomal contents, both from the host and the microbe, culminate in loss of viability of the ingested organism.
Topics: Cytoplasmic Granules; Humans; Hydrogen Peroxide; Hypochlorous Acid; Neutrophils; Oxidation-Reduction; Peroxidase; Phagocytosis; Phagosomes
PubMed: 24844117
DOI: 10.1111/cmi.12312 -
Molecular Cell Aug 2015Autophagy constitutes a prominent mechanism through which eukaryotic cells preserve homeostasis in baseline conditions and in response to perturbations of the... (Review)
Review
Autophagy constitutes a prominent mechanism through which eukaryotic cells preserve homeostasis in baseline conditions and in response to perturbations of the intracellular or extracellular microenvironment. Autophagic responses can be relatively non-selective or target a specific subcellular compartment. At least in part, this depends on the balance between the availability of autophagic substrates ("offer") and the cellular need of autophagic products or functions for adaptation ("demand"). Irrespective of cargo specificity, adaptive autophagy relies on a panel of sensors that detect potentially dangerous cues and convert them into signals that are ultimately relayed to the autophagic machinery. Here, we summarize the molecular systems through which specific subcellular compartments-including the nucleus, mitochondria, plasma membrane, reticular apparatus, and cytosol-convert homeostatic perturbations into an increased offer of autophagic substrates or an accrued cellular demand for autophagic products or functions.
Topics: Animals; Autophagy; Cell Membrane; Cell Nucleus; Endoplasmic Reticulum; Humans; Lysosomes; Membrane Potential, Mitochondrial; Mitochondria; Phagosomes
PubMed: 26295960
DOI: 10.1016/j.molcel.2015.07.021 -
Insect Biochemistry and Molecular... Jun 2019Phagocytosis is an evolutionarily conserved mechanism that plays a key role in both host defence and tissue homeostasis in multicellular organisms. A range of surface... (Review)
Review
Phagocytosis is an evolutionarily conserved mechanism that plays a key role in both host defence and tissue homeostasis in multicellular organisms. A range of surface receptors expressed on different cell types allow discriminating between self and non-self (or altered) material, thus enabling phagocytosis of pathogens and apoptotic cells. The phagocytosis process can be divided into four main steps: 1) binding of the phagocyte to the target particle, 2) particle internalization and phagosome formation, through remodelling of the plasma membrane, 3) phagosome maturation, and 4) particle destruction in the phagolysosome. In this review, we describe our present knowledge on phagocytosis in the fruit fly Drosophila melanogaster, assessing each of the key steps involved in engulfment of both apoptotic cells and bacteria. We also assess the physiological role of phagocytosis in host defence, development and tissue homeostasis.
Topics: Animals; Drosophila melanogaster; Immunity, Innate; Phagocytosis; Phagosomes
PubMed: 30953686
DOI: 10.1016/j.ibmb.2019.04.002 -
Communications Biology Oct 2023Phagosome maturation is critical for immune defense, defining whether ingested material is destroyed or converted into antigens. Sec22b regulates phagosome maturation,...
Phagosome maturation is critical for immune defense, defining whether ingested material is destroyed or converted into antigens. Sec22b regulates phagosome maturation, yet how has remained unclear. Here we show Sec22b tethers endoplasmic reticulum-phagosome membrane contact sites (MCS) independently of the known tether STIM1. Sec22b knockdown increases calcium signaling, phagolysosome fusion and antigen degradation and alters phagosomal phospholipids PI(3)P, PS and PI(4)P. Levels of PI(4)P, a lysosome docking lipid, are rescued by Sec22b re-expression and by expression of the artificial tether MAPPER but not the MCS-disrupting mutant Sec22b-P33. Moreover, Sec22b co-precipitates with the PS/PI(4)P exchange protein ORP8. Wild-type, but not mutant ORP8 rescues phagosomal PI(4)P and reduces antigen degradation. Sec22b, MAPPER and ORP8 but not P33 or mutant-ORP8 restores phagolysosome fusion in knockdown cells. These findings clarify an alternative mechanism through which Sec22b controls phagosome maturation and beg a reassessment of the relative contribution of Sec22b-mediated fusion versus tethering to phagosome biology.
Topics: Phagosomes; Phagocytosis; Endoplasmic Reticulum; Phosphatidylinositol Phosphates
PubMed: 37794132
DOI: 10.1038/s42003-023-05382-0 -
Frontiers in Cellular and Infection... 2017is a highly infectious Gram-negative bacterium and the causative agent of the zoonotic disease tularemia. This bacterial pathogen can infect a broad variety of animal... (Review)
Review
is a highly infectious Gram-negative bacterium and the causative agent of the zoonotic disease tularemia. This bacterial pathogen can infect a broad variety of animal species and can be transmitted to humans in numerous ways with various clinical outcomes. Although, possesses the capacity to infect numerous mammalian cell types, the macrophage constitutes the main intracellular niche, used for bacterial dissemination. To survive and multiply within infected macrophages, must imperatively escape from the phagosomal compartment. In the cytosol, the bacterium needs to control the host innate immune response and adapt its metabolism to this nutrient-restricted niche. Our laboratory has shown that intracellular mainly relied on host amino acid as major gluconeogenic substrates and provided evidence that the host metabolism was also modified upon infection. We will review here our current understanding of how copes with the available nutrient sources provided by the host cell during the course of infection.
Topics: Adaptation, Physiological; Amino Acids; Animals; Carbohydrate Metabolism; Cytosol; Francisella; Glycolysis; Host-Pathogen Interactions; Immunity, Innate; Macrophages; Phagosomes; Tularemia; Virulence Factors; Zoonoses
PubMed: 28401066
DOI: 10.3389/fcimb.2017.00096 -
Methods (San Diego, Calif.) Mar 2015Xenophagy is an autophagic phenomenon that specifically involves pathogens and other non-host entities. Although the understanding of the relationship between...
Xenophagy is an autophagic phenomenon that specifically involves pathogens and other non-host entities. Although the understanding of the relationship between autophagosomes and invading organisms has grown significantly in the past decade, the exact steps to confirm xenophagy has been not been thoroughly defined. Here we describe a methodical approach to confirming autophagy, its interaction with bacterial invasion, as well as the specific type of autophagic formation (i.e. autophagosome, autolysosome, phagolysosome). Further, we argue that xenophagy is not limited to pathogen interaction with autophagosome, but also non-microbial entities such as iron.
Topics: Autophagy; Brucella; Host-Pathogen Interactions; Humans; Infections; Lysosomes; Molecular Biology; Phagosomes
PubMed: 25497060
DOI: 10.1016/j.ymeth.2014.12.005