Anaerobic respiration of host-derived methionine sulfoxide protects intracellular Salmonella from the phagocyte NADPH oxidase
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ABSTRACT:
PROVIDER: PRJNA1043201 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26893861_1.fastq.gz | Fastqsanger.gz | |||
| SRR26893861_2.fastq.gz | Fastqsanger.gz | |||
| SRR26893862_1.fastq.gz | Fastqsanger.gz | |||
| SRR26893862_2.fastq.gz | Fastqsanger.gz | |||
| SRR26893863_1.fastq.gz | Fastqsanger.gz |
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Project description:Intracellular Salmonella experiencing oxidative stress downregulates aerobic respiration. To maintain cellular energetics during periods of oxidative stress, intracellular Salmonella must utilize terminal electron acceptors of lower energetic value than molecular oxygen. We show here that intracellular Salmonella undergoes anaerobic respiration during adaptation to the respiratory burst of the phagocyte NADPH oxidase in macrophages and in mice. Reactive oxygen species generated by phagocytes oxidize methionine, generating methionine sulfoxide. Anaerobic Salmonella uses the molybdenum cofactor-containing DmsABC enzymatic complex to reduce methionine sulfoxide. The enzymatic activity of the methionine sulfoxide reductase DmsABC helps Salmonella maintain an alkaline cytoplasm that supports the synthesis of the antioxidant hydrogen sulfide via cysteine desulfuration while providing a source of methionine and fostering redox balancing by associated dehydrogenases. Our investigations demonstrate that nontyphoidal Salmonella responding to oxidative stress exploits the anaerobic metabolism associated with dmsABC gene products, a pathway that has accrued inactivating mutations in human-adapted typhoidal serovars.
| S-EPMC11396582 | biostudies-literature
Project description:We report the changes in transcriptional landscape that occur under anaerobic conditions in the absence of a DMSO reductase in Salmonella enterica subsp. enterica serovar Typhimurium strain 14028s. By comparing the transcriptome of the parental, wild-type Salmonella to the transcriptome of a ∆dmsABC strain, we identified that there was a significant upregulation of SPI-2 genes in the ∆dmsABC strain.
2025-02-03 | GSE248315 | GEO
Project description:The phagocyte NADPH oxidase is critical for host defence, and EROS (Essential for Reactive Oxygen Species) protein is indispensable for expression of its gp91phox-p22phox heterodimer. EROS deficiency in humans is a recently described cause of chronic granulomatous disease (CGD), but its mechanism of action remains unknown. We show EROS binds the immature 58kDa gp91phox directly prior to glycosylation and heme incorporation, thus preventing its degradation. EROS interacts with the oligosaccharyl transferase complex (OST) present at the endoplasmic reticulum. Inhibition of the OST complex suppresses EROS-mediated stabilisation of the 58kDa, providing insight into the early steps of gp91phox biosynthesis. EROS also regulates the purine receptors P2X7 and P2X1 through direct interactions. Accordingly, lack of EROS results in markedly abnormal P2X7 signalling, inflammasome activation and T cell responses. The loss of both the phagocyte respiratory burst and P2X7 signalling lead to resistance to influenza infection. Our work identifies EROS as the first described highly selective chaperone controlling key proteins in innate and adaptive immunity. It has profound implications for immune physiology, immunodeficiency and gene therapy.
2022-11-30 | PXD025149 | Pride
Project description:The role of phagocyte NADPH Oxidase (NOX2) in modulating the antimicrobial and inflammatory functions of mouse neutrophils
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Project description:Methionine sulfoxide reductase A (MsrA) catalyzes the reduction of methionine sulfoxide to methionine and is specific for the S epimer of methionine sulfoxide. The enzyme participates in defense against oxidative stresses by reducing methionine sulfoxide residues in proteins back to methionine. Because oxidation of methionine residues is reversible, this covalent modification could also function as a mechanism for cellular regulation, provided there exists a stereospecific methionine oxidase. We show that MsrA itself is a stereospecific methionine oxidase, producing S-methionine sulfoxide as its product. MsrA catalyzes its own autooxidation as well as oxidation of free methionine and methionine residues in peptides and proteins. When functioning as a reductase, MsrA fully reverses the oxidations which it catalyzes.
| S-EPMC3127874 | biostudies-literature
Project description:Phagocyte oxidase plays an essential role in the first line of host defense against pathogens. It oxidizes intracellular NADPH to reduce extracellular oxygen to produce superoxide anions that participate in pathogen killing. The resting phagocyte oxidase is a heterodimeric complex formed by two transmembrane proteins NOX2 and p22. Despite the physiological importance of this complex, its structure remains elusive. Here, we reported the cryo-EM structure of the functional human NOX2-p22 complex in nanodisc in the resting state. NOX2 shows a canonical 6-TM architecture of NOX and p22 has four transmembrane helices. M3, M4, and M5 of NOX2, and M1 and M4 helices of p22 are involved in the heterodimer formation. Dehydrogenase (DH) domain of NOX2 in the resting state is not optimally docked onto the transmembrane domain, leading to inefficient electron transfer and NADPH binding. Structural analysis suggests that the cytosolic factors might activate the NOX2-p22 complex by stabilizing the DH in a productive docked conformation.
| S-EPMC9711523 | biostudies-literature
Project description:ANCA-activated phagocytes cause vasculitis and necrotizing crescentic GN (NCGN). ANCA-induced phagocyte NADPH oxidase (Phox) may contribute by generating tissue-damaging reactive oxygen species. We tested an alternative hypothesis, in which Phox restrains inflammation by downregulating caspase-1, thereby reducing IL-1β generation and limiting NCGN. In an antimyeloperoxidase (anti-MPO) antibody-mediated disease model, mice transplanted with either gp91(phox)-deficient or p47(phox)-deficient bone marrow showed accelerated disease with increased crescents, necrosis, glomerular monocytes, and renal IL-1β levels compared with mice transplanted with wild-type bone marrow. IL-1β receptor blockade abrogated aggravated NCGN in gp91(phox)-deficient mice. In vitro, challenge with anti-MPO antibody strongly enhanced caspase-1 activity and IL-1β generation in gp91(phox)-deficient and p47(phox)-deficient monocytes compared with wild-type monocytes. This enhanced IL-1β generation was abrogated when caspase-1 was blocked. ANCA-induced superoxide and IL-1β generation were inversely related in human monocytes. Furthermore, transplantation of gp91(phox)/caspase-1 double-deficient bone marrow rescued the accelerated NCGN phenotype in gp91(phox) bone marrow-deficient mice. These results suggest that Phox-generated reactive oxygen species downregulate caspase-1, thereby keeping the inflammasome in check and limiting ANCA-induced inflammation. IL-1 receptor blockade may provide a promising strategy in NCGN, whereas our data question the benefit of antioxidants.
| S-EPMC4310655 | biostudies-literature
Project description:This project contains the COFRADIC data of two experimental set-ups (swapped labeling) in which methionine sulfoxides were identified in Jurkat cells stressed with hydrogen peroxide. We used a SILAC set-up in which cells were labeled with 12C5 methionine or with 13C5 methionine. One of the set-ups was treated with hydrogen peroxide, the other with H2O. Following lysis proteins were mixed in a 1/1 ratio. We then performed our methionine sulfoxide validation protocol onto the sample identifying methionine sulfoxides in the stressed Jurkat cells.
2011-03-18 | PRD000395 | Pride
Project description:Essential for reactive oxygen species (EROS) protein is a recently identified molecular chaperone of NOX2 (gp91phox), the catalytic subunit of phagocyte NADPH oxidase. Deficiency in EROS is a recently identified cause for chronic granulomatous disease, a genetic disorder with recurrent bacterial and fungal infections. Here, we report a cryo-EM structure of the EROS-NOX2-p22phox heterotrimeric complex at an overall resolution of 3.56Å. EROS and p22phox are situated on the opposite sides of NOX2, and there is no direct contact between them. EROS associates with NOX2 through two antiparallel transmembrane (TM) α-helices and multiple β-strands that form hydrogen bonds with the cytoplasmic domain of NOX2. EROS binding induces a 79° upward bend of TM2 and a 48° backward rotation of the lower part of TM6 in NOX2, resulting in an increase in the distance between the two hemes and a shift of the binding site for flavin adenine dinucleotide (FAD). These conformational changes are expected to compromise superoxide production by NOX2, suggesting that the EROS-bound NOX2 is in a protected state against activation. Phorbol myristate acetate, an activator of NOX2 in vitro, is able to induce dissociation of NOX2 from EROS with concurrent increase in FAD binding and superoxide production in a transfected COS-7 model. In differentiated neutrophil-like HL-60, the majority of NOX2 on the cell surface is dissociated with EROS. Further studies are required to delineate how EROS dissociates from NOX2 during its transport to cell surface, which may be a potential mechanism for regulation of NOX2 activation.
| S-EPMC11161758 | biostudies-literature
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