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Cell Host & Microbe Aug 2021Engagement of LC3-associated phagocytosis (LAP) in response to the uptake of certain particles modulates innate immune responses. Now in Cell Host and Microbe,...
Engagement of LC3-associated phagocytosis (LAP) in response to the uptake of certain particles modulates innate immune responses. Now in Cell Host and Microbe, Akoumianaki et al. (2021) show how a regulatory role of IL-6 on LAP may be at the core of susceptibility to secondary infection during severe sepsis.
Topics: Autophagy; Humans; Immunity, Innate; Microtubule-Associated Proteins; Phagocytosis; Phagosomes
PubMed: 34384524
DOI: 10.1016/j.chom.2021.07.010 -
Autophagy 2015
Topics: Animals; Autophagy; Humans; Lysosomes; Mitochondria; Neurons; Phagosomes
PubMed: 25831012
DOI: 10.1080/15548627.2015.1009790 -
The EMBO Journal Oct 2023The regulation of autophagy initiation is a key step in autophagosome biogenesis. However, our understanding of the molecular mechanisms underlying the stepwise assembly...
The regulation of autophagy initiation is a key step in autophagosome biogenesis. However, our understanding of the molecular mechanisms underlying the stepwise assembly of ATG proteins during this process remains incomplete. The Rab GTPase Ypt1/Rab1 is recognized as an essential autophagy regulator. Here, we identify Atg23 and Atg17 as binding partners of Ypt1, with their direct interaction proving crucial for the stepwise assembly of autophagy initiation complexes. Disruption of Ypt1-Atg23 binding results in significantly reduced Atg9 interactions with Atg11, Atg13, and Atg17, thus preventing the recruitment of Atg9 vesicles to the phagophore assembly site (PAS). Likewise, Ypt1-Atg17 binding contributes to the PAS recruitment of Ypt1 and Atg1. Importantly, we found that Ypt1 is phosphorylated by TOR at the Ser174 residue. Converting this residue to alanine blocks Ypt1 phosphorylation by TOR and enhances autophagy. Conversely, the Ypt1 phosphorylation mimic impairs both PAS recruitment and activation of Atg1, thus inhibiting subsequent autophagy. Thus, we propose TOR-mediated Ypt1 as a multifunctional assembly factor that controls autophagy initiation via its regulation of the stepwise assembly of ATG proteins.
Topics: Autophagy; Autophagy-Related Proteins; Phagosomes; Phosphorylation; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 37635626
DOI: 10.15252/embj.2022112814 -
The Journal of Cell Biology Jan 2018How do organelles coordinate their unique molecular identities between their cytosolic-facing surface membranes and their interior? In this issue, Naufer et al. (2017....
How do organelles coordinate their unique molecular identities between their cytosolic-facing surface membranes and their interior? In this issue, Naufer et al. (2017. https://doi.org/10.1083/jcb.201702179) discover an intriguing link between phagosome acidification and lipid signposts on their outer membrane.
Topics: Cell Membrane; Humans; Membrane Lipids; Organelles; Phagocytosis; Phagosomes
PubMed: 29233864
DOI: 10.1083/jcb.201711134 -
Nature Communications Nov 2023Autophagosomes are double-membrane vesicles generated intracellularly to encapsulate substrates for lysosomal degradation during autophagy. Phase separated p62 body...
Autophagosomes are double-membrane vesicles generated intracellularly to encapsulate substrates for lysosomal degradation during autophagy. Phase separated p62 body plays pivotal roles during autophagosome formation, however, the underlying mechanisms are still not fully understood. Here we describe a spatial membrane gathering mode by which p62 body functions in autophagosome formation. Mass spectrometry-based proteomics reveals significant enrichment of vesicle trafficking components within p62 body. Combining cellular experiments and biochemical reconstitution assays, we confirm the gathering of ATG9 and ATG16L1-positive vesicles around p62 body, especially in Atg2ab DKO cells with blocked lipid transfer and vesicle fusion. Interestingly, p62 body also regulates ATG9 and ATG16L vesicle trafficking flux intracellularly. We further determine the lipid contents associated with p62 body via lipidomic profiling. Moreover, with in vitro kinase assay, we uncover the functions of p62 body as a platform to assemble ULK1 complex and invigorate PI3KC3-C1 kinase cascade for PI3P generation. Collectively, our study raises a membrane-based working model for multifaceted p62 body in controlling autophagosome biogenesis, and highlights the interplay between membraneless condensates and membrane vesicles in regulating cellular functions.
Topics: Autophagosomes; Autophagy; Macroautophagy; Phagosomes; Autophagy-Related Proteins; Lipids
PubMed: 37957156
DOI: 10.1038/s41467-023-42829-8 -
Immunological Reviews Mar 2023Neutrophils are the most abundant circulating leukocyte and are crucial to the initial innate immune response to infection. One of their key pathogen-eliminating... (Review)
Review
Neutrophils are the most abundant circulating leukocyte and are crucial to the initial innate immune response to infection. One of their key pathogen-eliminating mechanisms is phagocytosis, the process of particle engulfment into a vacuole-like structure called the phagosome. The antimicrobial activity of the phagocytic process results from a collaboration of multiple systems and mechanisms within this organelle, where a complex interplay of ion fluxes, pH, reactive oxygen species, and antimicrobial proteins creates a dynamic antimicrobial environment. This complexity, combined with the difficulties of studying neutrophils ex vivo, has led to gaps in our knowledge of how the neutrophil phagosome optimizes pathogen killing. In particular, controversy has arisen regarding the relative contribution and integration of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived antimicrobial agents and granule-delivered antimicrobial proteins. Clinical syndromes arising from dysfunction in these systems in humans allow useful insight into these mechanisms, but their redundancy and synergy add to the complexity. In this article, we review the current knowledge regarding the formation and function of the neutrophil phagosome, examine new insights into the phagosomal environment that have been permitted by technological advances in recent years, and discuss aspects of the phagocytic process that are still under debate.
Topics: Humans; Neutrophils; Phagosomes; Phagocytosis; Phagocytes; Reactive Oxygen Species
PubMed: 36440666
DOI: 10.1111/imr.13173 -
Molecules and Cells Jan 2018Atg5 and Atg7 have long been considered as essential molecules for autophagy. However, we found that cells lacking these molecules still form autophagic vacuoles and... (Review)
Review
Atg5 and Atg7 have long been considered as essential molecules for autophagy. However, we found that cells lacking these molecules still form autophagic vacuoles and perform autophagic protein degradation when subjected to certain stressors. During this unconventional autophagy pathway, autophagosomes appeared to be generated in a Rab9-dependent manner by the fusion of vesicles derived from the -Golgi and late endosomes. Therefore, mammalian autophagy can occur via at least two different pathways; the Atg5/Atg7-dependent conventional pathway and an Atg5/Atg7-independent alternative pathway.
Topics: Animals; Autophagosomes; Autophagy; Autophagy-Related Protein 5; Autophagy-Related Protein 7; Humans; Lysosomes; Microtubule-Associated Proteins; Models, Biological; Phagosomes
PubMed: 29370693
DOI: 10.14348/molcells.2018.2215 -
International Journal of Medical... Jan 2018Phagocytosis is essential for uptake and elimination of pathogenic microorganisms. Autophagy is a highly conserved mechanism for incorporation of cellular constituents... (Review)
Review
Phagocytosis is essential for uptake and elimination of pathogenic microorganisms. Autophagy is a highly conserved mechanism for incorporation of cellular constituents to replenish nutrients by degradation. Recently, parts of the autophagy machinery - above all microtubule-associated protein 1 light chain 3 (LC3) - were found to be specifically recruited to phagosomal membranes resulting in phagosome-lysosome fusion and efficient degradation of internalized cargo in a process termed LC3-associated phagocytosis (LAP). Many pathogenic bacterial, fungal and parasitic microorganisms reside within LAP-targeted single-membrane phagosomes or vacuoles after infection of host cells. In this minireview we describe the state of knowledge on the interaction of pathogens with LAP or LAP-like pathways and report on various pathogens that have evolved strategies to circumvent degradation in LAP compartments.
Topics: Animals; Bacteria; Fungi; Humans; Immune Evasion; Microtubule-Associated Proteins; Parasites; Phagocytosis; Phagosomes; Vacuoles
PubMed: 29169848
DOI: 10.1016/j.ijmm.2017.10.014 -
Virulence Dec 2019Autophagy is a conserved and fundamental cellular process mainly to recycle or eliminate dysfunctional cellular organelles or proteins. As a response to cellular stress,... (Review)
Review
Autophagy is a conserved and fundamental cellular process mainly to recycle or eliminate dysfunctional cellular organelles or proteins. As a response to cellular stress, autophagy is used as a defense mechanism to combat the infection with pathogenic bacteria. However, many intracellular bacteria have developed diverse mechanisms to evade recognition, to manipulate the autophagic pathway, and to hijack the autophagosomal compartment for replication. In this review, we discuss recent understandings on how bacteria interact with host autophagy.
Topics: Autophagy; Bacteria; Cytoplasm; Host-Pathogen Interactions; Humans; Lysosomes; Phagosomes
PubMed: 30978154
DOI: 10.1080/21505594.2019.1602020 -
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