Identification of novel proteins associated with xenophagy in host cell
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens (human)
SUBMITTER: Takashi Nozawa, Atsuko Minowa-Nozawa
PROVIDER: PXD038868 | JPOST Repository | Wed Dec 21 00:00:00 GMT 2022
REPOSITORIES: jPOST
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Project description:Almost all intracellular bacteria invade host cells through endocytic membrane trafficking. Bacteria that invade through endocytosis are rapidly transported to degradative organelles, therefore bacterial pathogens have evolved strategies to modulate intracellular bactericidal pathways during infection for survival and proliferation. On the other hand, the host cell also has a defensive system (xenophagy, a type of selective autophagy) against pathogens escaping from endosomes.
2023-05-23 | PXD042419 | JPOST Repository
Project description:Commensal bacteria influence host physiology, including immune responses, without invading host tissues. We show that proteins from segmented filamentous bacteria (SFB), which are immunomodulatory commensal microbes, are transferred into intestinal epithelial cells by adhesion-directed endocytosis that is distinct from the clathrin-dependent endocytosis of invasive pathogens. SFB transfer microbial cell wall-associated proteins, including an antigen that stimulates mucosal Th17 cell differentiation, into the cytosol of epithelial cells. Removal of CDC42 activity in vivo led to disruption of endocytosis induced by SFB, decreased epithelial antigen acquisition with consequent loss of immune modulation by SFB-specific CD4 T cells and mucosal Th17 cells. Our findings indicate direct communication between a resident gut microbe and the host and show that intestinal epithelial cells acquire antigens from commensal bacteria for generation of T-cell responses to the resident microbiota.
2019-01-10 | GSE124848 | GEO
Project description:Background During infection by intracellular pathogens, a highly complex interplay occurs between the infected cell trying to degrade the invader and the pathogen which actively manipulates the host cell to enable survival and proliferation. Many intracellular pathogens pose important threats to human health and major efforts have been undertaken to better understand the host-pathogen interactions that eventually determine the outcome of the infection. Over the last decades, the unicellular eukaryote Dictyostelium discoideum has become an established infection model, serving as a surrogate macrophage that can be infected with a wide range of intracellular pathogens. In this study, we use high-throughput RNA-sequencing to analyze the transcriptional response of D. discoideum when infected with Mycobacterium marinum and Legionella pneumophila. The results were compared to available data from human macrophages. Results The majority of the transcriptional regulation triggered by the two pathogens was found to be unique for each bacterial challenge. Hallmark transcriptional signatures were identified for each infection, e.g. induction of endosomal sorting complexes required for transport (ESCRT) and autophagy genes in response to M. marinum and inhibition of genes associated with the translation machinery and energy metabolism in response to L. pneumophila. However, a common response to the pathogenic bacteria was also identified, which was not induced by non-pathogenic food bacteria. Finally, comparison with available data sets of regulation in human monocyte derived macrophages shows that the elicited response in D. discoideum recapitulates what has been observed in human immune cells in response to Mycobacterium tuberculosis and L. pneumophila. Conclusions Our study presents high-throughput characterization of D. discoideum transcriptional response to intracellular pathogens using RNA-seq. We demonstrate that the transcriptional response is in essence distinct to each pathogen and to a large extent recapitulate the regulation in human macrophages after infection by mycobacteria and L. pneumophila. This indicates that host-pathogen interactions are evolutionary conserved, derived from the early interactions between free-living phagocytic cells and bacteria. Taken together, our results strengthen the use of D. discoideum as a general infection model.
2019-11-04 | GSE132461 | GEO
Project description:The phylum Apicomplexa comprises an ancient group of early divergent eukaryotes, including some of the most deadly pathogens of medical and veterinary importance. Plasmodium species are responsible for malaria, which causes as many as 700,000 deaths per year, while Toxoplasma gondii chronically infects up to 30% of the human population, with immunocompromised patients and pregnant women at risk for adverse outcomes, such as toxoplasmic encephalitis and spontaneous abortion, respectively. T. gondii is considered a model system not only for its pathogenic relatives but also for intracellular parasitism and infection biology in general. T. gondii has common eukaryotic organelles, including the nucleus, endoplasmic reticulum (ER), and a single Golgi stack, but also specific secretory organelles named dense granules, micronemes, and rhoptries that contain parasite-derived factors required for host infection. Rhoptries and micronemes are formed de novo during parasite replication, and this process requires significant protein and lipid trafficking through the secretory pathway. The trafficking mechanisms employed by T. gondii retain several typical eukaryote components as well as evolving divergent features. Protein trafficking of this parasite is mediated by entry into a canonical ER followed by vesicle packaging through a single Golgi complex. Post-Golgi protein sorting to specific organelles requires the function of dynamin-related protein B, which is involved in fission events. Downstream Rab-GTPases function throughout the parasite secretory pathway. T. gondii soluble N-ethylmaleimide-sensitive-factor attachment protein receptor (SNARE) proteins in docking and fusion at target membranes have also been described. However, unlike in mammalian cells, T. gondii ER is reduced so that the nuclear envelope itself contributes to a substantial proportion of its total volume. Whereas in mammalian cells hundreds of Golgi stacks occupy the perinuclear area, the Golgi apparatus is limited to a single discrete structure in T.gondii. The post-Golgi system also named the endosome-like compartment (ELC) is involved in the trafficking of microneme proteins. The ELC is decorated by the small GTPases, Rab5 and Rab7, which are typically associated with the endosomal system. Nevertheless, classical endocytosis has not yet been validated in T. gondii. This parasite has no lysosomes; rather the parasite harbors acidic vesicles that were thought to be precursors of the rhoptry organelles. The parasite lacks most components of endosomal sorting complexes (ESCRT), which are known for their roles in forming multivesicular bodies that deliver ubiquitinated membrane proteins and lipids to lysosomes for degradation. The machinery required for caveogenesis and caveola-dependent invaginations have not yet been identified in the parasite. Furthermore, while evidence of conventional clathrin-dependent endocytosis by T.gondii is lacking, clathrin is present exclusively in post-Golgi compartments where its function is restricted to post-Golgi trafficking, and the uptake of cytosol proteins by the tachyzoites of T. gondii has recently been described using an endocytosis assay. However, the mechanisms underlying the events of this unconventional endocytosis in the parasite remain to be determined. Clearly, the secretory pathway of T. gondii can be considered a stripped-down version of the more complex trafficking machinery that characterizes higher eukaryotes. Despite this minimal trafficking machinery, the parasites actively rely on a membrane vesicle formation and transport during its intracellular lifecycle; however, to date, comparatively little is known about the mechanisms involved in trafficking pathways in T. gondii. We previously reported a T. gondii sortilin-like receptor (TgSORTLR) that regulates protein transport and is essential for apical secretory organelle biogenesis and host infection17. Moreover, the C-terminal tail of TgSORTLR was shown to be involved in recruiting many cytosolic cargo proteins including two homologues of the core retromer components, Vps26 and Vps35, which are known to regulate retrograde transport from endosomes to the trans-Golgi Network (TGN) in yeast and mammals. Here, we report that a singular architecture with a trimer Vps35-Vps26-Vps29 core complex acts as the major cargo endosomal recycling machinery and is required for parasite integrity and more specifically for secretory organelle biogenesis and maintenance of a multiple ligand-binding transporter at the T. gondii membrane. Our findings provide strong evidence that the unconventional TgSORTLR-containing endosome-like compartment is involved in distinct mechanisms for the delivery of major retromer-dependent cargo. In this current work, we demonstrate a definitive role for the endocytic recycling pathway in T. gondii pathogenesis.
2016-04-12 | PXD003603 | Pride
Project description:Intracellular trafficking pathways in eukaryotic cells are essential to maintain organelle identity and structure, and to regulate cell communication with its environment. Shigella flexneri invades and subverts the human colonic epithelium by the injection of virulence factors through a type 3 secretion system (T3SS). In this work we report the multiple effects of two S. flexneri effectors, IpaJ and VirA, which target small GTPases of the Arf and Rab families, consequently inhibiting several intracellular trafficking pathways. IpaJ and VirA induce large-scale impairment of host protein secretion and block the recycling of surface receptors. Moreover, these two effectors decrease clathrin-dependent and -independent endocytosis. Therefore, S. flexneri infection induces a global blockage of host cell intracellular transport, affecting the exchange between cells and their external environment. The combined action of these effectors disorganizes the epithelial cell polarity, disturbs epithelial barrier integrity, promotes multiple invasion events and enhances the pathogen capacity to penetrate into the colonic tissue in vivo.
2019-06-04 | PXD012291 | Pride
Project description:Intracellular pathogens requires efficient mechanism adapting the environment inside of host cells. Here we show that the transcriptomes of the cellular mycobacterium tuberculosis and of those released from the infected macrophage cells contain a large fraction of human transcripts by RNA polymerase II. Uptake of host pre-mRNAs is coincident with the co-localization of M. tuberculosis with nuclear membrane. The infective M. tuberculosis selectively uptakes snoRNAs.The intracellular pathogens has a preferable capability in taking pre-mRNAs. The host transcripts are not generally spliced nor translated.We suggest that the intracellular bacterium has acquired a mechanism to take transcripts from the host cell nuclus as its own nutrient supply and may help them to survive with hosts.
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