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Journal of Cell Science Feb 2019Classically, canonical autophagy has been considered a survival mechanism initiated in response to nutrient insufficiency. We now understand that autophagy functions in... (Review)
Review
Classically, canonical autophagy has been considered a survival mechanism initiated in response to nutrient insufficiency. We now understand that autophagy functions in multiple scenarios where it is necessary to maintain homeostasis. Recent evidence has established that a variety of non-canonical functions for autophagy proteins are mechanistically and functionally distinct from autophagy. LC3-associated phagocytosis (LAP) is one such novel function for autophagy proteins and is a contributor to immune regulation and inflammatory responses across various cell and tissue types. Characterized by the conjugation of LC3 family proteins to phagosome membranes, LAP uses a portion of the canonical autophagy machinery, following ligation of surface receptors that recognize a variety of cargos including pathogens, dying cells, soluble ligands and protein aggregates. However, instead of affecting canonical autophagy, manipulation of the LAP pathway alters immune activation and inflammatory responses. In this Cell Science at a Glance article and the accompanying poster, we detail the divergence of this distinctive mechanism from that of canonical autophagy by comparing and contrasting shared and unique components of each pathway.
Topics: Animals; Autophagy; Humans; Macrophages; Microtubule-Associated Proteins; Phagocytosis; Phagosomes
PubMed: 30787029
DOI: 10.1242/jcs.222984 -
International Journal of Molecular... Jan 2019Epidemiological data from the Center of Disease Control (CDC) and the World Health Organization (WHO) statistics in 2017 show that 10.0 million people around the world... (Review)
Review
Epidemiological data from the Center of Disease Control (CDC) and the World Health Organization (WHO) statistics in 2017 show that 10.0 million people around the world became sick with tuberculosis. (MTB) is an intracellular parasite that mainly attacks macrophages and inhibits their apoptosis. It can become a long-term infection in humans, causing a series of pathological changes and clinical manifestations. In this review, we summarize innate immunity including the inhibition of antioxidants, the maturation and acidification of phagolysosomes and especially the apoptosis and autophagy of macrophages. Besides, we also elaborate on the adaptive immune response and the formation of granulomas. A thorough understanding of these escape mechanisms is of major importance for the prevention, diagnosis and treatment of tuberculosis.
Topics: Animals; Apoptosis; Autophagy; Humans; Immune Evasion; Mycobacterium tuberculosis; Oxidative Stress; Phagosomes
PubMed: 30650615
DOI: 10.3390/ijms20020340 -
Frontiers in Immunology 2020Phagocytosis is a cellular process for ingesting and eliminating particles larger than 0.5 μm in diameter, including microorganisms, foreign substances, and apoptotic... (Review)
Review
Phagocytosis is a cellular process for ingesting and eliminating particles larger than 0.5 μm in diameter, including microorganisms, foreign substances, and apoptotic cells. Phagocytosis is found in many types of cells and it is, in consequence an essential process for tissue homeostasis. However, only specialized cells termed professional phagocytes accomplish phagocytosis with high efficiency. Macrophages, neutrophils, monocytes, dendritic cells, and osteoclasts are among these dedicated cells. These professional phagocytes express several phagocytic receptors that activate signaling pathways resulting in phagocytosis. The process of phagocytosis involves several phases: i) detection of the particle to be ingested, ii) activation of the internalization process, iii) formation of a specialized vacuole called phagosome, and iv) maturation of the phagosome to transform it into a phagolysosome. In this review, we present a general view of our current understanding on cells, phagocytic receptors and phases involved in phagocytosis.
Topics: Apoptosis; Humans; Models, Immunological; Pathogen-Associated Molecular Pattern Molecules; Phagocytes; Phagocytosis; Phagosomes; Receptors, Complement; Receptors, IgG; Receptors, Immunologic; Receptors, Pattern Recognition; Signal Transduction
PubMed: 32582172
DOI: 10.3389/fimmu.2020.01066 -
Immunological Reviews Mar 2015Macrophages and neutrophils play a decisive role in host responses to intracellular bacteria including the agent of tuberculosis (TB), Mycobacterium tuberculosis as they... (Review)
Review
Macrophages and neutrophils play a decisive role in host responses to intracellular bacteria including the agent of tuberculosis (TB), Mycobacterium tuberculosis as they represent the forefront of innate immune defense against bacterial invaders. At the same time, these phagocytes are also primary targets of intracellular bacteria to be abused as host cells. Their efficacy to contain and eliminate intracellular M. tuberculosis decides whether a patient initially becomes infected or not. However, when the infection becomes chronic or even latent (as in the case of TB) despite development of specific immune activation, phagocytes have also important effector functions. Macrophages have evolved a myriad of defense strategies to combat infection with intracellular bacteria such as M. tuberculosis. These include induction of toxic anti-microbial effectors such as nitric oxide and reactive oxygen intermediates, the stimulation of microbe intoxication mechanisms via acidification or metal accumulation in the phagolysosome, the restriction of the microbe's access to essential nutrients such as iron, fatty acids, or amino acids, the production of anti-microbial peptides and cytokines, along with induction of autophagy and efferocytosis to eliminate the pathogen. On the other hand, M. tuberculosis, as a prime example of a well-adapted facultative intracellular bacterium, has learned during evolution to counter-balance the host's immune defense strategies to secure survival or multiplication within this otherwise hostile environment. This review provides an overview of innate immune defense of macrophages directed against intracellular bacteria with a focus on M. tuberculosis. Gaining more insights and knowledge into this complex network of host-pathogen interaction will identify novel target sites of intervention to successfully clear infection at a time of rapidly emerging multi-resistance of M. tuberculosis against conventional antibiotics.
Topics: Animals; Cell Communication; Host-Pathogen Interactions; Humans; Immunity, Innate; Lysosomes; Macrophage Activation; Macrophages; Metals; Mycobacterium tuberculosis; Phagocytes; Phagocytosis; Phagosomes; Tuberculosis
PubMed: 25703560
DOI: 10.1111/imr.12266 -
Cells Dec 2021Mitochondria are multifunctional subcellular organelles essential for cellular energy homeostasis and apoptotic cell death. It is, therefore, crucial to maintain... (Review)
Review
Mitochondria are multifunctional subcellular organelles essential for cellular energy homeostasis and apoptotic cell death. It is, therefore, crucial to maintain mitochondrial fitness. Mitophagy, the selective removal of dysfunctional mitochondria by autophagy, is critical for regulating mitochondrial quality control in many physiological processes, including cell development and differentiation. On the other hand, both impaired and excessive mitophagy are involved in the pathogenesis of different ageing-associated diseases such as neurodegeneration, cancer, myocardial injury, liver disease, sarcopenia and diabetes. The best-characterized mitophagy pathway is the PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent pathway. However, other Parkin-independent pathways are also reported to mediate the tethering of mitochondria to the autophagy apparatuses, directly activating mitophagy (mitophagy receptors and other E3 ligases). In addition, the existence of molecular mechanisms other than PINK1-mediated phosphorylation for Parkin activation was proposed. The adenosine5'-monophosphate (AMP)-activated protein kinase (AMPK) is emerging as a key player in mitochondrial metabolism and mitophagy. Beyond its involvement in mitochondrial fission and autophagosomal engulfment, its interplay with the PINK1-Parkin pathway is also reported. Here, we review the recent advances in elucidating the canonical molecular mechanisms and signaling pathways that regulate mitophagy, focusing on the early role and spatial specificity of the AMPK/ULK1 axis.
Topics: AMP-Activated Protein Kinases; Animals; Autophagy-Related Protein-1 Homolog; Humans; Mitophagy; Models, Biological; Phagosomes; Ubiquitin-Protein Ligases
PubMed: 35011593
DOI: 10.3390/cells11010030 -
Nature Immunology Feb 2021Type 1 conventional dendritic (cDC1) cells are necessary for cross-presentation of many viral and tumor antigens to CD8 T cells. cDC1 cells can be identified in mice and...
Type 1 conventional dendritic (cDC1) cells are necessary for cross-presentation of many viral and tumor antigens to CD8 T cells. cDC1 cells can be identified in mice and humans by high expression of DNGR-1 (also known as CLEC9A), a receptor that binds dead-cell debris and facilitates XP of corpse-associated antigens. Here, we show that DNGR-1 is a dedicated XP receptor that signals upon ligand engagement to promote phagosomal rupture. This allows escape of phagosomal contents into the cytosol, where they access the endogenous major histocompatibility complex class I antigen processing pathway. The activity of DNGR-1 maps to its signaling domain, which activates SYK and NADPH oxidase to cause phagosomal damage even when spliced into a heterologous receptor and expressed in heterologous cells. Our data reveal the existence of innate immune receptors that couple ligand binding to endocytic vesicle damage to permit MHC class I antigen presentation of exogenous antigens and to regulate adaptive immunity.
Topics: Animals; Antigen Presentation; Cell Death; Coculture Techniques; Cross-Priming; Dendritic Cells; HEK293 Cells; Histocompatibility Antigens Class I; Humans; Lectins, C-Type; Ligands; Mice; NADPH Oxidases; Phagosomes; Phosphorylation; RAW 264.7 Cells; Reactive Oxygen Species; Receptors, Immunologic; Receptors, Mitogen; Signal Transduction; Syk Kinase; T-Lymphocytes
PubMed: 33349708
DOI: 10.1038/s41590-020-00824-x -
Autophagy 2015Metformin activates both PRKA and SIRT1. Furthermore, autophagy is induced by either the PRKA-MTOR-ULK1 or SIRT1-FOXO signaling pathways. We aimed to elucidate the...
Metformin activates both PRKA and SIRT1. Furthermore, autophagy is induced by either the PRKA-MTOR-ULK1 or SIRT1-FOXO signaling pathways. We aimed to elucidate the mechanism by which metformin alleviates hepatosteatosis by examining the molecular interplay between SIRT1, PRKA, and autophagy. ob/ob mice were divided into 3 groups: one with ad libitum feeding of a standard chow diet, one with 300 mg/kg intraperitoneal metformin injections, and one with 3 g/d caloric restriction (CR) for a period of 4 wk. Primary hepatocytes or HepG2 cells were treated with oleic acid (OA) plus high glucose in the absence or presence of metformin. Both CR and metformin significantly improved body weight and glucose homeostasis, along with hepatic steatosis, in ob/ob mice. Furthermore, CR and metformin both upregulated SIRT1 expression and also stimulated autophagy induction and flux in vivo. Metformin also prevented OA with high glucose-induced suppression of both SIRT1 expression and SIRT1-dependent activation of autophagy machinery, thereby alleviating intracellular lipid accumulation in vitro. Interestingly, metformin treatment upregulated SIRT1 expression and activated PRKA even after siRNA-mediated knockdown of PRKAA1/2 and SIRT1, respectively. Taken together, these results suggest that metformin alleviates hepatic steatosis through PRKA-independent, SIRT1-mediated effects on the autophagy machinery.
Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Blood Glucose; Body Weight; Caloric Restriction; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus, Type 2; Down-Regulation; Fatty Liver; Hep G2 Cells; Hepatocytes; Humans; Lipid Metabolism; Liver; Metformin; Mice, Inbred C57BL; Mice, Obese; Models, Biological; Oleic Acid; Phagosomes; Signal Transduction; Sirtuin 1; Up-Regulation
PubMed: 25484077
DOI: 10.4161/15548627.2014.984271 -
Cells Nov 2021Trogocytosis is a mode of internalization of a part of a live cell by nibbling and is mechanistically distinct from phagocytosis, which implies internalization of a... (Review)
Review
Trogocytosis is a mode of internalization of a part of a live cell by nibbling and is mechanistically distinct from phagocytosis, which implies internalization of a whole cell or a particle. Trogocytosis has been demonstrated in a broad range of cell types in multicellular organisms and is also known to be involved in a plethora of functions. In immune cells, trogocytosis is involved in the "cross-dressing" between antigen presenting cells and T cells, and is thus considered to mediate intercellular communication. On the other hand, trogocytosis has also been reported in a variety of unicellular organisms including the protistan (protozoan) parasite . ingests human T cell line by trogocytosis and acquires complement resistance and cross-dresses major histocompatibility complex (MHC) class I on the cell surface. Furthermore, trogocytosis and trogocytosis-like phenomena (nibbling of a live cell, not previously described as trogocytosis) have also been reported in other parasitic protists such as , , , and free-living amoebae. Thus, trogocytosis is conserved in diverse eukaryotic supergroups as a means of intercellular communication. It is depicting the universality of trogocytosis among eukaryotes. In this review, we summarize our current understanding of trogocytosis in unicellular organisms, including the history of its discovery, taxonomical distribution, roles, and molecular mechanisms.
Topics: Animals; Entamoeba histolytica; Eukaryota; Models, Biological; Parasites; Phagosomes; Trogocytosis
PubMed: 34831198
DOI: 10.3390/cells10112975 -
Virulence Dec 2023Tularaemia is a zoonotic disease caused by the Gram-negative bacterium, . Depending on its entry route into the organism, causes different diseases, ranging from... (Review)
Review
Tularaemia is a zoonotic disease caused by the Gram-negative bacterium, . Depending on its entry route into the organism, causes different diseases, ranging from life-threatening pneumonia to less severe ulceroglandular tularaemia. Various strains with different geographical distributions exhibit different levels of virulence. is an intracellular bacterium that replicates primarily in the cytosol of the phagocytes. The main virulence attribute of is the type 6 secretion system (T6SS) and its effectors that promote escape from the phagosome. In addition, has evolved a peculiar envelope that allows it to escape detection by the immune system. In this review, we cover tularaemia, different strains, and their pathogenicity. We particularly emphasize the intracellular life cycle, associated virulence factors, and metabolic adaptations. Finally, we present how largely escapes immune detection to be one of the most infectious and lethal bacterial pathogens.
Topics: Humans; Francisella tularensis; Virulence; Tularemia; Virulence Factors; Phagosomes
PubMed: 37941380
DOI: 10.1080/21505594.2023.2274638 -
Journal of Molecular Histology Feb 2021Apoptosis and clearance of dead cells is highly evolutionarily conserved from nematode to humans, which is crucial to the growth and development of multicellular... (Review)
Review
Apoptosis and clearance of dead cells is highly evolutionarily conserved from nematode to humans, which is crucial to the growth and development of multicellular organism. Fail to remove apoptotic cells often lead to homeostasis imbalance, fatal autoimmune diseases, and neurodegenerative diseases. Small ubiquitin-related modifiers (SUMOs) modification is a post-translational modification of ubiquitin proteins mediated by the sentrin-specific proteases (SENPs) family. SUMO modification is widely involved in many cellular biological process, and abnormal SUMO modification is also closely related to many major human diseases. Recent researches have revealed that SUMO modification event occurs during apoptosis and clearance of apoptotic cells, and plays an important role in the regulation of apoptotic signaling pathways. This review summarizes some recent progress in the revelation of regulatory mechanisms of these pathways and provides some potential researching hotpots of the SUMO modification regulation to apoptosis.
Topics: Apoptosis; Humans; Mitochondria; Phagosomes; Protein Processing, Post-Translational; Signal Transduction; Small Ubiquitin-Related Modifier Proteins
PubMed: 33225418
DOI: 10.1007/s10735-020-09924-2