-
Cell Apr 2014Autophagy is directed by numerous distinct autophagy-related (Atg) proteins. These transmit starvation-induced signals to lipids and regulatory proteins and assemble a... (Review)
Review
Autophagy is directed by numerous distinct autophagy-related (Atg) proteins. These transmit starvation-induced signals to lipids and regulatory proteins and assemble a double-membrane autophagosome sequestering bulk cytoplasm and/or selected cargos destined for degradation upon autophagosome fusion with a vacuole or lysosome. This Review discusses the structural mechanisms by which Atg proteins sense membrane curvature, mediate a PI(3)P-signaling cascade, and utilize autophagy-specific ubiquitin-like protein cascades to tether proteins to autophagosomal membranes. Recent elucidation of molecular interactions enabling vesicle nucleation, elongation, and cargo recruitment provides insights into how dynamic protein-protein and protein-membrane interactions may dictate size, shape, and contents of autophagosomes.
Topics: Animals; Autophagy; Cell Membrane; Humans; Membrane Proteins; Phagosomes
PubMed: 24725401
DOI: 10.1016/j.cell.2014.01.070 -
Journal of Cell Science Apr 2015Autophagy is an essential homeostatic process for degrading cellular cargo. Aging organelles and protein aggregates are degraded by the autophagosome-lysosome pathway,... (Review)
Review
Autophagy is an essential homeostatic process for degrading cellular cargo. Aging organelles and protein aggregates are degraded by the autophagosome-lysosome pathway, which is particularly crucial in neurons. There is increasing evidence implicating defective autophagy in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and Huntington's disease. Recent work using live-cell imaging has identified autophagy as a predominantly polarized process in neuronal axons; autophagosomes preferentially form at the axon tip and undergo retrograde transport back towards the cell body. Autophagosomes engulf cargo including damaged mitochondria (mitophagy) and protein aggregates, and subsequently fuse with lysosomes during axonal transport to effectively degrade their internalized cargo. In this Cell Science at a Glance article and the accompanying poster, we review recent progress on the dynamics of the autophagy pathway in neurons and highlight the defects observed at each step of this pathway during neurodegeneration.
Topics: Animals; Autophagy; Humans; Neurodegenerative Diseases; Neurons; Phagosomes
PubMed: 25829512
DOI: 10.1242/jcs.161216 -
Frontiers in Immunology 2021The rapid and efficient phagocytic clearance of apoptotic cells, termed efferocytosis, is a critical mechanism in the maintenance of tissue homeostasis. Removal of... (Review)
Review
The rapid and efficient phagocytic clearance of apoptotic cells, termed efferocytosis, is a critical mechanism in the maintenance of tissue homeostasis. Removal of apoptotic cells through efferocytosis prevents secondary necrosis and the resultant inflammation caused by the release of intracellular contents. The importance of efferocytosis in homeostasis is underscored by the large number of inflammatory and autoimmune disorders, including atherosclerosis and systemic lupus erythematosus, that are characterized by defective apoptotic cell clearance. Although mechanistically similar to the phagocytic clearance of pathogens, efferocytosis differs from phagocytosis in that it is immunologically silent and induces a tissue repair response. Efferocytes face unique challenges resulting from the internalization of apoptotic cells, including degradation of the apoptotic cell, dealing with the extra metabolic load imposed by the processing of apoptotic cell contents, and the coordination of an anti-inflammatory, pro-tissue repair response. This review will discuss recent advances in our understanding of the cellular response to apoptotic cell uptake, including trafficking of apoptotic cell cargo and antigen presentation, signaling and transcriptional events initiated by efferocytosis, the coordination of an anti-inflammatory response and tissue repair, unique cellular metabolic responses and the role of efferocytosis in host defense. A better understanding of how efferocytic cells respond to apoptotic cell uptake will be critical in unraveling the complex connections between apoptotic cell removal and inflammation resolution and maintenance of tissue homeostasis.
Topics: Antigen Presentation; Apoptosis; Gene Expression Regulation; Homeostasis; Humans; Inflammation; Phagocytes; Phagocytosis; Phagosomes; Signal Transduction
PubMed: 33959122
DOI: 10.3389/fimmu.2021.631714 -
Immunity May 2005Phagocytosis requires receptor-mediated recognition of particles, usually in the guise of infectious agents and apoptotic cells. Phagosomes fuse with lysosomes to... (Review)
Review
Phagocytosis requires receptor-mediated recognition of particles, usually in the guise of infectious agents and apoptotic cells. Phagosomes fuse with lysosomes to generate phagolysosomes, which play a key role in enzymatic digestion of the internalized contents into component parts. Recent findings indicate that a simple paradigm of a single cognate receptor interaction that guides the phagosome to phagolysosome formation belies the complexity of combinatorial receptor recognition and diversity of phagosome function. In fact, phagosomes are comprised of hundreds of proteins that play a key role in deciphering the contents of the phagosome and in defining host response. In this review we discuss how the challenge of recognizing diverse molecular patterns is met by combinatorial interactions between phagocytic receptors. Furthermore, these combinations are dynamic and both sculpt the balance between a proinflammatory or anti-inflammatory response and direct phagosome diversity. We also indicate an important role for genetically tractable model organisms in defining key components of this evolutionarily conserved process.
Topics: Adaptation, Physiological; Animals; Antigen Presentation; Apoptosis; Autophagy; Humans; Immunity, Innate; Models, Immunological; Opsonin Proteins; Phagocytes; Phagocytosis; Phagosomes; Receptors, Cell Surface; Signal Transduction
PubMed: 15894272
DOI: 10.1016/j.immuni.2005.05.002 -
Journal of Immunology (Baltimore, Md. :... Jul 2012Autophagy is a fundamental eukaryotic process with multiple cytoplasmic homeostatic roles, recently expanded to include unique stand-alone immunological functions and... (Review)
Review
Autophagy is a fundamental eukaryotic process with multiple cytoplasmic homeostatic roles, recently expanded to include unique stand-alone immunological functions and interactions with nearly all parts of the immune system. In this article, we review this growing repertoire of autophagy roles in innate and adaptive immunity and inflammation. Its unique functions include cell-autonomous elimination of intracellular microbes facilitated by specific receptors. Other intersections of autophagy with immune processes encompass effects on inflammasome activation and secretion of its substrates, including IL-1β, effector and regulatory interactions with TLRs and Nod-like receptors, Ag presentation, naive T cell repertoire selection, and mature T cell development and homeostasis. Genome-wide association studies in human populations strongly implicate autophagy in chronic inflammatory disease and autoimmune disorders. Collectively, the unique features of autophagy as an immunological process and its contributions to other arms of the immune system represent a new immunological paradigm.
Topics: Animals; Antigen Presentation; Autophagy; Bacterial Infections; Cytosol; Humans; Inflammasomes; Inflammation; Phagosomes; Receptors, Pattern Recognition
PubMed: 22723639
DOI: 10.4049/jimmunol.1102108 -
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 -
The Journal of Pathology Jun 2010Autophagy is a fundamental and phylogenetically conserved self-degradation process that is characterized by the formation of double-layered vesicles (autophagosomes)... (Review)
Review
Autophagy is a fundamental and phylogenetically conserved self-degradation process that is characterized by the formation of double-layered vesicles (autophagosomes) around intracellular cargo for delivery to lysosomes and proteolytic degradation. The increasing significance attached to autophagy in development and disease in higher eukaryotes has placed greater importance on the validation of reliable, meaningful and quantitative assays to monitor autophagy in live cells and in vivo in the animal. To date, the detection of processed LC3B-II by western blot or fluorescence studies, together with electron microscopy for autophagosome formation, have been the mainstays for autophagy detection. However, LC3 expression levels can vary markedly between different cell types and in response to different stresses, and there is also concern that over-expression of tagged versions of LC3 to facilitate imaging and detection of autophagy interferes with the process itself. In addition, the realization that it is not sufficient to monitor static levels of autophagy but to measure 'autophagic flux' has driven the development of new or modified approaches to detecting autophagy. Here, we present a critical overview of current methodologies to measure autophagy in cells and in animals.
Topics: Animals; Autophagy; Biomarkers; Flow Cytometry; Humans; Lysosomes; Microscopy, Electron; Microscopy, Fluorescence; Microtubule-Associated Proteins; Phagosomes
PubMed: 20225337
DOI: 10.1002/path.2694 -
International Journal of Molecular... Feb 2023Phagocytosis is one of the most polarised of all cellular activities. Both the stimulus (the target for phagocytosis) and the response (its internalisation) are focussed... (Review)
Review
Phagocytosis is one of the most polarised of all cellular activities. Both the stimulus (the target for phagocytosis) and the response (its internalisation) are focussed at just one part of the cell. At the locus, and this locus alone, pseudopodia form a phagocytic cup around the particle, the cytoskeleton is rearranged, the plasma membrane is reorganised, and a new internal organelle, the phagosome, is formed. The effect of signals from the stimulus must, thus, both be complex and yet be restricted in space and time to enable an effective focussed response. While many aspects of phagocytosis are being uncovered, the mechanism for the restriction of signalling or the effects of signalling remains obscure. In this review, the details of the problem of restricting chemical intracellular signalling are presented, with a focus on diffusion into the cytosol and of signalling lipids along the plasma membrane. The possible ways in which simple diffusion is overcome so that the restriction of signalling and effective phagocytosis can be achieved are discussed in the light of recent advances in imaging, biophysics, and cell biochemistry which together are providing new insights into this area.
Topics: Phagocytosis; Phagosomes; Pseudopodia; Cytoskeleton; Cytosol
PubMed: 36769146
DOI: 10.3390/ijms24032825