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Mycobacterium tuberculosis is protected from NADPH oxidase and LC3-associated phagocytosis by the LCP protein CpsA

ABSTRACT: Mycobacterium tuberculosis is protected from NADPH oxidase and LC3-associated phagocytosis by the LCP protein CpsA

PROVIDER: PRJNA595319 | ENA |

REPOSITORIES: ENA

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Mycobacterium tuberculosis is protected from NADPH oxidase and LC3-associated phagocytosis by the LCP protein CpsA

Project description:Mycobacterium tuberculosis’success as a pathogen comes from itsability to evade degradation by macrophages. Normally macro-phages clear microorganisms that activate pathogen-recognitionreceptors (PRRs) through a lysosomal-trafficking pathway called“LC3-associated phagocytosis”(LAP). AlthoughM.tuberculosisac-tivates numerous PRRs, for reasons that are poorly understoodLAP does not substantially contribute toM.tuberculosiscontrol.LAP depends upon reactive oxygen species (ROS) generated byNADPH oxidase, butM.tuberculosisfails to generate a robustoxidative response. Here, we show that CpsA, a LytR-CpsA-Psr(LCP) domain-containing protein, is required forM.tuberculosisto evade killing by NADPH oxidase and LAP. Unlike phagosomescontaining wild-type bacilli, phagosomes containing theΔcpsAmutant recruited NADPH oxidase, produced ROS, associated withLC3, and matured into antibacterial lysosomes. Moreover, CpsAwas sufficient to impair NADPH oxidase recruitment to fungal par-ticles that are normally cleared by LAP. Intracellular survival of theΔcpsAmutant was largely restored in macrophages missing LAPcomponents (Nox2,Rubicon,Beclin,Atg5,Atg7,orAtg16L1) butnot in macrophages defective in a related, canonical autophagypathway (Atg14,Ulk1,orcGAS). TheΔcpsAmutant was highlyimpaired in vivo, and its growth was partially restored in micedeficient in NADPH oxidase,Atg5,orAtg7, demonstrating thatCpsA makes a significant contribution to the resistance ofM.tu-berculosisto NADPH oxidase and LC3 trafficking in vivo. Overall,our findings reveal an essential role of CpsA in innate immuneevasion and suggest that LCP proteins have functions beyond theirpreviously known role in cell-wall metabolism.

2019-12-13 | GSE141931 | GEO

Project description:Phagocytosis-related NADPH oxidase 2 subunit gp91phox contributes to neurodegeneration after repeated systemic challenge with lipopolysaccharides

| PRJNA642158 | ENA

Transcription profiling of Salmonella typhimurium isolated from mice bone marrow derived macrophages with and without NADPH oxidase

Project description:NADPH dependent phagocytic oxidase, by producing hydroxyradicals such as hydrogen peroxide, is essential for host defense against Salmonella infection. We used gene array analysis to identify Salmonella enterica serovar Typhimurium genes regulated by NADPH dependent phagocytic oxidase intracellularly in comparison to those expressed in vitro by hydrogen peroxide.

2007-05-02 | E-MEXP-1089 | biostudies-arrayexpress

Cytosolic Accumulation of Small Nucleolar RNAs (snoRNAs) is Dynamically Regulated by NADPH Oxidase

Project description:Small nucleolar RNAs (snoRNAs) guide nucleotide modifications of cellular RNAs in the nucleus. We have previously shown that box C/D snoRNAs from the Rpl13a locus are unexpected mediators of physiologic oxidative stress, independent of their predicted ribosomal RNA modifications. Here, we demonstrate that oxidative stress induced by doxorubicin causes rapid cytoplasmic accumulation of the Rpl13a snoRNAs through a mechanism that requires superoxide and a nuclear splice variant of NADPH oxidase. RNA-sequencing analysis reveals that box C/D snoRNAs as a class are present in the cytoplasm, where their levels are dynamically regulated by NADPH oxidase. These findings suggest that snoRNAs may orchestrate the response to environmental stress through molecular interactions outside of the nucleus.

2015-03-20 | GSE67050 | GEO

NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice

Project description:NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice

| PRJNA752129 | ENA

Uncoupling of IL-6 signaling and LC3-associated phagocytosis (LAP) drives immunoparalysis during sepsis

Project description:Immune deactivation of phagocytes is a central event in pathogenesis of sepsis that remains molecularly unexplored. In particular, how cytokine deregulation induced by sepsis compromises the microbicidal activity of phagocytes and results in secondary infections by opportunistic bacterial and fungal pathogens is incompletely understood. Herein, we identify a master regulatory role of cytokine signaling on LC3-associated phagocytosis (LAP), and reveal that uncoupling of these two processes during sepsis induces immunoparalysis in monocytes/macrophages.

2022-05-01 | GSE174183 | GEO

Regulation of myeloid function by LC3-associated phagocytosis promotes tumor immune tolerance

Project description:Targeting autophagy in cancer cells and in the tumor microenvironment are current goals of cancer therapy. However, components of canonical autophagy play roles in other biological processes, adding complexity to this goal. One such alternative function of autophagy proteins is LC3-associated phagocytosis (LAP), which functions in phagosome maturation and subsequent signaling events. Here we show that impairment of LAP in the myeloid compartment, rather than canonical autophagy, induces control of tumor growth by tumor-associated macrophages (TAM) upon phagocytosis of dying tumor cells. Single cell RNAseq analysis revealed that defects in LAP induce pro-inflammatory gene expression and trigger STING-mediated type I interferon responses in TAM. We found that the anti-tumor effects of LAP impairment require tumor-infiltrating T cells, dependent upon the STING and the type I interferon response. Therefore, autophagy proteins in the myeloid cells of the tumor microenvironment contribute to immune suppression of T lymphocytes by effecting LAP.

2018-09-15 | GSE118019 | GEO

Regulation of myeloid function by LC3-associated phagocytosis promotes tumor immune tolerance

Project description:Regulation of myeloid function by LC3-associated phagocytosis promotes tumor immune tolerance

| PRJNA484019 | ENA

LC3-associated phagocytosis of neutrophils trigger tumor ferroptotic cell death in glioblastoma

Project description:Necrosis is commonly found in various solid tumors and predicts worse outcome. Chronic ischemia can initiate tumor necrosis, but how the damaged tissue further expands is unclear. Previous studies found that neutrophils associate with necrosis and could contribute to necrosis development in glioblastoma (GBM) by transferring myeloperoxidase (MPO)-containing granules into tumor cells and inducing tumor cell ferroptosis. How the neutrophilic granule transfer occurs is unknown. Here, through an unbiased small molecule screen, we found that statins can inhibit neutrophil-induced tumor cell death by blocking the neutrophilic content transfer into tumor cells. Surprisingly, we found that neutrophils are engulfed by tumor cells before they are fragmented and release the MPO-containing contents in tumor cells. This process involves LC3-associated phagocytosis (LAP) and can be blocked by inhibiting the Vps34-UVRAG-containing PI3K complex. Inhibition of MPO or depletion of Vps34 in an orthotopic xenograft GBM mouse model reduced necrosis formation and allowed tumor-bearing mice to survive longer. Therefore, this study revealed that the neutrophilic granule transfer involves LAP-mediated neutrophil internalization, which then triggers tumor ferroptotic cell death in glioblastoma. Blocking this process may improve prognosis of GBM.

2024-04-29 | GSE263766 | GEO

Project description:Here, we investigated the role of mononuclear phagocytes associated nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX-2) in inflammatory neurodegeneration. Cybb-deficient mice NOX-2 knock-out (KO) and control wild type (WT) mice were treated intraperitoneally daily over four consecutive days with 1 µg/gbw/day LPS. Repeated LPS injections led to inflammation and neuronal loss in the brains of WT mice, which was attenuated after knockout of NOX-2. Transcriptome analysis by RNA-seq of total brain tissue indicated increased LPS-induced upregulation of genes belonging to the reactive oxygen species (ROS) and reactive nitrogen species (RNS) production, complement and lysosome activation as well as apoptosis and necroptosis in WT compared to NOX-2 KO mice.

2020-08-03 | GSE153369 | GEO

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