Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE118019 | GEO | 2018/09/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

Changes to the global transcriptome in human U2OS and BJ cell lines as a result of STING activation

Project description:Activation of Stimulator of interferon genes (STING) is well known to upregulate inflammation through canonical TBK1 signaling. STING is recently found to activate noncanonical functions through its transmembrane proton channel. Whether STING stimulates any transcription programs through its channel is unknown. In this study, we identified the transcription factor EB (TFEB) as a downstream effector of the STING channel. TFEB is a transcriptional regulator of lysosomal biogenesis and autophagy. Using RNA sequencing approaches, we confirmed that STING activated transcriptional upregulation of lysosomal biogenesis and autophagy independently of TBK1.

2024-09-19 | GSE254174 | GEO

PDCD6 modulates LC3-associated phagocytosis-mediated antimicrobial defense by regulating lactate metabolism

Project description:LC3-associated phagocytosis (LAP) is critical in host defense against invading pathogens, but the molecular mechanism for LAP activation is still unclear. Here, we find programmed cell death 6 (PDCD6) as a negative regulator of LAP. PDCD6 deficiency in mice and macrophages induces enhanced bactericidal activity and LAP formation. In parallel, lactate dehydrogenase A (LDHA) activity and lactate production is induced in macrophages challenged with bacteria, Zymosan or Pam3CSK4, while genetic ablation or pharmacological inhibition of LDHA reduces lactate levels and impairs bactericidal activity in vivo and in vitro. Mechanistically, PDCD6 interacts with LDHA to downregulate lactate metabolism, leading to reduced RUBCN lactylation at lysine33 (K33). By contrast, PDCD6-deficiency increases RUBCN lactylation, thereby promotes RUBCN interaction with VPS34, LAP formation, and protective responses. Our results thus suggest a PDCD6-LDHA-lactate-RUBCN axis of innate immunity regulation that may both contribute to protection from infectious diseases and serve as targets for therapeutic development.

2024-10-18 | PXD056047 | Pride

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

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

MiR-471-5p–Dependent Regulation of Phagocytosis/Autophagy-Associated Proteins

Project description:Phagocytic clearance of apoptotic germ cells by Sertoli cells is vital for germ cell development and differentiation. Using a tissue-specific miRNA transgenic mouse model, we show that interaction between miR-471-5p and autophagy member proteins regulates clearance of apoptotic germ cells via LC3-associated phagocytosis (LAP).

2017-11-01 | GSE99500 | GEO

Cyclic-Di-Nucleotides Trigger ULK1 (ATG1) Phosphorylation of STING to Prevent Sustained Innate Immune Signaling

Project description:Activation of the STING (Stimulator of Interferon Genes) pathway by microbial or self-DNA, as well as cyclic di nucleotides (CDN), results in the induction of numerous genes that suppress pathogen replication and facilitate adaptive immunity. However, sustained gene transcription is rigidly prevented to avoid lethal STING-dependent pro-inflammatory disease by mechanisms that remain unknown. We demonstrate here that after autophagy-dependent STING delivery of TBK1 (TANK-binding kinase 1) to endosomal/lysosomal compartments and activation of transcription factors IRF3 (interferon regulatory factors 3) and NF-κB (nuclear factor kappa beta), that STING is subsequently phosphorylated by serine/threonine UNC-51-like kinase (ULK1/ATG1) and IRF3 function is suppressed. ULK1 activation occurred following disassociation from its repressor adenine monophosphate activated protein kinase (AMPK), and was elicited by CDN’S generated by the cGAMP synthase, cGAS. Thus, while CDN’s may initially facilitate STING function, they subsequently trigger negative-feedback control of STING activity, thus preventing the persistent transcription of innate immune genes. Total RNA obtained from primary STING deficient mouse embryonic fibroblast reconstituted with mSTING (W), S365A variant (A), or S365D variant (D). These cells were transfected with dsDNA (ISD) for 3 hours.

2013-10-10 | E-GEOD-51199 | biostudies-arrayexpress

Bulk RNA-seq of FACS sorted astrocytes upon microglial depletion

Project description:As the professional phagocyte in the central nervous system (CNS), microglia are the primary scavenger removing cell corpses. The failure of microglia in debris clearance influences the normal CNS function. Meanwhile, microglia undergo turnover during the whole lifespan. If dead microglia are not timely removed, accumulated corpses may influence the CNS function. The microglial corpse clearance is hereby crucial for CNS homeostasis. However, the underlying mechanism remains obscure. In this study, we investigated how microglial corpses are removed. We found that microglial corpses are mainly phagocytosed by astrocytes, mediated by C4b opsonization. Then engulfed microglial fragments are degraded in astrocytes via the RUBICON-dependent LC3-associated phagocytosis (LAP), a form of non-canonical autophagy. The interference of the C4b-mediated engulfment and its subsequent LAP disrupt the microglial debris removal and degradation, respectively. Together, we elucidated cellular and molecular mechanisms of microglial debris removal, extending the knowledge on how the CNS homeostasis is maintained.

2022-09-01 | GSE171321 | GEO

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

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

| PRJNA728689 | ENA

Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity

Project description:Chronic activation of inflammatory pathways and suppressed interferon are hallmarks of immunosuppressive tumors. Previous studies have shown that CD11b integrin agonists could enhance anti-tumor immunity through myeloid reprograming, but the underlying mechanisms remain unclear. Herein we find that CD11b agonists alter tumor-associated macrophage (TAM) phenotypes by repressing NF-κB signaling and activating interferon gene expression simultaneously. Repression of NF-κB signaling involves degradation of p65 protein and is context independent. In contrast, CD11b agonism induces STING/STAT1 pathway-mediated interferon gene expression through FAK-mediated mitochondrial dysfunction, with the magnitude of induction dependent on the tumor microenvironment and amplified by cytotoxic therapies. Using tissues from phase I clinical studies, we demonstrate that GB1275 treatment activates STING and STAT1 signaling in TAMs in human tumors. These findings suggest potential mechanism-based therapeutic strategies for CD11b agonists and identify patient populations more likely to benefit.

2023-03-21 | GSE220959 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data