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  1. AU="Härtlova, Anetta"
  2. AU="Ghanem, Ahmed I"
  3. AU="Yue Lu"
  4. AU="Pincus, Laura B"
  5. AU="Ibrahim, Nashwan"
  6. AU=Bray Molly S AU=Bray Molly S
  7. AU="Bregy, Amadé"
  8. AU=Kaper J B
  9. AU="León-Ramón, Susana"
  10. AU="Simpson, Andrew"
  11. AU="Peters, Wibke"
  12. AU="Malik, Sajid Ali"
  13. AU="V, Gomathi"

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  1. Artikel ; Online: Assessing the Phagosome Proteome by Quantitative Mass Spectrometry.

    Dueñas, Maria Emilia / Marín-Rubio, José Luis / Peltier-Heap, Julien / Hartlova, Anetta / Trost, Matthias

    Methods in molecular biology (Clifton, N.J.)

    2023  Band 2692, Seite(n) 361–374

    Abstract: The process of phagocytosis involves a series of defined steps, including the formation of a new intracellular organelle, i.e., the phagosome, and the maturation of the phagosome by fusion with endosomes and lysosomes to produce an acidic and proteolytic ...

    Abstract The process of phagocytosis involves a series of defined steps, including the formation of a new intracellular organelle, i.e., the phagosome, and the maturation of the phagosome by fusion with endosomes and lysosomes to produce an acidic and proteolytic environment in which the pathogens are degraded. Phagosome maturation is associated with significant changes in the proteome of phagosomes due to the acquisition of new proteins or enzymes, post-translational modifications of existing proteins, as well as other biochemical changes that ultimately lead to the degradation or processing of the phagocytosed particle. Phagosomes are highly dynamic organelles formed by the uptake of particles through phagocytic innate immune cells; thus characterization of the phagosomal proteome is essential to understand the mechanisms controlling innate immunity, as well as vesicle trafficking. In this chapter, we describe how novel quantitative proteomics methods, such as using tandem mass tag (TMT) labelling or acquiring label-free data using data-independent acquisition (DIA), can be applied for the characterization of protein composition of phagosomes in macrophages.
    Mesh-Begriff(e) Proteome/metabolism ; Phagosomes/metabolism ; Phagocytosis ; Macrophages/metabolism ; Mass Spectrometry
    Chemische Substanzen Proteome
    Sprache Englisch
    Erscheinungsdatum 2023-06-26
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-3338-0_23
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: The role of innate immunity and inflammation in Parkinson´s disease.

    Öberg, Maria / Fabrik, Ivo / Fabrikova, Daniela / Zehetner, Nina / Härtlova, Anetta

    Scandinavian journal of immunology

    2021  Band 93, Heft 5, Seite(n) e13022

    Abstract: For many years, it was postulated that the brain is the organ behind the barrier with an autonomous need for its maintenance. This view has been changed by the concept that the central nervous system is sensitive to the immune processes occurring in the ... ...

    Abstract For many years, it was postulated that the brain is the organ behind the barrier with an autonomous need for its maintenance. This view has been changed by the concept that the central nervous system is sensitive to the immune processes occurring in the periphery as well as to the infiltration of peripheral immune cells. However, how the immune system might contribute to the development of neurodegenerative diseases, such as Parkinson's disease (PD), remains unclear. PD is a chronic neurodegenerative disorder that affects motor and cognitive functions. Although the precise cause of PD is unknown, studies in both mice and human suggest that alterations in the innate immunity may play a critical role in modulating PD progression. Here, we review recent advancements in our understanding of inflammation and the innate immune mechanisms in PD pathology.
    Mesh-Begriff(e) Animals ; Central Nervous System/immunology ; Humans ; Immunity, Innate/immunology ; Inflammation/immunology ; Mice ; Microglia/metabolism ; Neuroimmunomodulation/immunology ; Parkinson Disease/immunology ; Parkinson Disease/pathology ; alpha-Synuclein/metabolism
    Chemische Substanzen alpha-Synuclein
    Sprache Englisch
    Erscheinungsdatum 2021-03-22
    Erscheinungsland England
    Dokumenttyp Journal Article ; Review
    ZDB-ID 120476-2
    ISSN 1365-3083 ; 0300-9475
    ISSN (online) 1365-3083
    ISSN 0300-9475
    DOI 10.1111/sji.13022
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  3. Artikel ; Online: Lung macrophages utilize unique cathepsin K-dependent phagosomal machinery to degrade intracellular collagen.

    Fabrik, Ivo / Bilkei-Gorzo, Orsolya / Öberg, Maria / Fabrikova, Daniela / Fuchs, Johannes / Sihlbom, Carina / Göransson, Melker / Härtlova, Anetta

    Life science alliance

    2023  Band 6, Heft 4

    Abstract: Resident tissue macrophages are organ-specialized phagocytes responsible for the maintenance and protection of tissue homeostasis. It is well established that tissue diversity is reflected by the heterogeneity of resident tissue macrophage origin and ... ...

    Abstract Resident tissue macrophages are organ-specialized phagocytes responsible for the maintenance and protection of tissue homeostasis. It is well established that tissue diversity is reflected by the heterogeneity of resident tissue macrophage origin and phenotype. However, much less is known about tissue-specific phagocytic and proteolytic macrophage functions. Here, using a quantitative proteomics approach, we identify cathepsins as key determinants of phagosome maturation in primary peritoneum-, lung-, and brain-resident macrophages. The data further uncover cathepsin K (CtsK) as a molecular marker for lung phagosomes required for intracellular protein and collagen degradation. Pharmacological blockade of CtsK activity diminished phagosomal proteolysis and collagenolysis in lung-resident macrophages. Furthermore, profibrotic TGF-β negatively regulated CtsK-mediated phagosomal collagen degradation independently from classical endocytic-proteolytic pathways. In humans, phagosomal CtsK activity was reduced in COPD lung macrophages and non-COPD lung macrophages exposed to cigarette smoke extract. Taken together, this study provides a comprehensive map of how peritoneal, lung, and brain tissue environment shapes phagosomal composition, revealing CtsK as a key molecular determinant of lung phagosomes contributing to phagocytic collagen clearance in lungs.
    Mesh-Begriff(e) Humans ; Cathepsin K/metabolism ; Collagen/metabolism ; Lung ; Macrophages/metabolism ; Phagosomes/metabolism
    Chemische Substanzen Cathepsin K (EC 3.4.22.38) ; Collagen (9007-34-5) ; CTSK protein, human (EC 3.4.22.38)
    Sprache Englisch
    Erscheinungsdatum 2023-01-25
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2575-1077
    ISSN (online) 2575-1077
    DOI 10.26508/lsa.202201535
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  4. Artikel ; Online: Macrophages and scavenger receptors in obesity-associated non-alcoholic liver fatty disease (NAFLD).

    Kragh Petersen, Sine / Bilkei-Gorzo, Orsolya / Govaere, Olivier / Härtlova, Anetta

    Scandinavian journal of immunology

    2020  Band 92, Heft 5, Seite(n) e12971

    Abstract: With an increase in sedentary lifestyle and dietary over nutrition, obesity has become one of the major public health problems worldwide and is a prevalent predisposing risk factor to non-alcoholic fatty liver disease (NAFLD), the most common chronic ... ...

    Abstract With an increase in sedentary lifestyle and dietary over nutrition, obesity has become one of the major public health problems worldwide and is a prevalent predisposing risk factor to non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in Western developed countries. NAFLD represents a series of diseased states ranging from non-alcoholic fatty liver (NAFL) to steatohepatitis (NASH), which can lead to fibrosis and eventually to cirrhosis and hepatocellular carcinoma. Currently, the only effective treatment to cure end-stage liver disease is liver transplantation. Macrophages have been reported to play a crucial role in the progression of NAFLD, thereby are a potential target for therapy. In this review, we discuss the current knowledge on the role of macrophages and inflammatory signalling pathways associated with obesity and chronic liver inflammation, and their contribution to NAFLD development and progression.
    Mesh-Begriff(e) Carcinoma, Hepatocellular/complications ; Carcinoma, Hepatocellular/immunology ; Carcinoma, Hepatocellular/metabolism ; Disease Progression ; Fatty Liver/complications ; Fatty Liver/immunology ; Fatty Liver/metabolism ; Humans ; Liver Cirrhosis/complications ; Liver Cirrhosis/immunology ; Liver Cirrhosis/metabolism ; Liver Neoplasms/complications ; Liver Neoplasms/immunology ; Liver Neoplasms/metabolism ; Macrophages/immunology ; Macrophages/metabolism ; Non-alcoholic Fatty Liver Disease/complications ; Non-alcoholic Fatty Liver Disease/immunology ; Non-alcoholic Fatty Liver Disease/metabolism ; Obesity/complications ; Obesity/immunology ; Obesity/metabolism ; Receptors, Scavenger/immunology ; Receptors, Scavenger/metabolism
    Chemische Substanzen Receptors, Scavenger
    Sprache Englisch
    Erscheinungsdatum 2020-09-21
    Erscheinungsland England
    Dokumenttyp Journal Article ; Review
    ZDB-ID 120476-2
    ISSN 1365-3083 ; 0300-9475
    ISSN (online) 1365-3083
    ISSN 0300-9475
    DOI 10.1111/sji.12971
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  5. Artikel ; Online: Regulation of phagosome functions by post-translational modifications: a new paradigm.

    Dean, Paul / Heunis, Tiaan / Härtlova, Anetta / Trost, Matthias

    Current opinion in chemical biology

    2018  Band 48, Seite(n) 73–80

    Abstract: Phagosomes are highly dynamic organelles formed by the uptake of particles through phagocytic innate immune cells such as macrophages. Their key roles in microbe elimination and antigen presentation make them essential for innate and adaptive immunity. ... ...

    Abstract Phagosomes are highly dynamic organelles formed by the uptake of particles through phagocytic innate immune cells such as macrophages. Their key roles in microbe elimination and antigen presentation make them essential for innate and adaptive immunity. However, phagosomes are also important for tissue homeostasis as even in healthy individuals billions of dead cells are phagocytosed each day. In this short review, we highlight how the use of latex beads as inert baits for phagocytosis and subsequent analysis by proteomics has changed our understanding of the phagosome. We further discuss recent data on post-translational modifications such as phosphorylation and ubiquitylation that regulate phagosome functions and demonstrate that the phagosome is not only a 'degradative organelle' but also serves as a subcellular signalling platform.
    Mesh-Begriff(e) Animals ; Humans ; Phagosomes/chemistry ; Phagosomes/metabolism ; Phosphorylation ; Protein Processing, Post-Translational ; Proteins/analysis ; Proteins/metabolism ; Proteomics/methods ; Signal Transduction ; Ubiquitination
    Chemische Substanzen Proteins
    Sprache Englisch
    Erscheinungsdatum 2018-11-24
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1439176-4
    ISSN 1879-0402 ; 1367-5931
    ISSN (online) 1879-0402
    ISSN 1367-5931
    DOI 10.1016/j.cbpa.2018.11.001
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  6. Artikel: Simvastatin therapy attenuates memory deficits that associate with brain monocyte infiltration in chronic hypercholesterolemia.

    Don-Doncow, Nicholas / Vanherle, Lotte / Matthes, Frank / Petersen, Sine Kragh / Matuskova, Hana / Rattik, Sara / Härtlova, Anetta / Meissner, Anja

    NPJ aging and mechanisms of disease

    2021  Band 7, Heft 1, Seite(n) 19

    Abstract: Evidence associates cardiovascular risk factors with unfavorable systemic and neuro-inflammation and cognitive decline in the elderly. Cardiovascular therapeutics (e.g., statins and anti-hypertensives) possess immune-modulatory functions in parallel to ... ...

    Abstract Evidence associates cardiovascular risk factors with unfavorable systemic and neuro-inflammation and cognitive decline in the elderly. Cardiovascular therapeutics (e.g., statins and anti-hypertensives) possess immune-modulatory functions in parallel to their cholesterol- or blood pressure (BP)-lowering properties. How their ability to modify immune responses affects cognitive function is unknown. Here, we examined the effect of chronic hypercholesterolemia on inflammation and memory function in Apolipoprotein E (ApoE) knockout mice and normocholesterolemic wild-type mice. Chronic hypercholesterolemia that was accompanied by moderate blood pressure elevations associated with apparent immune system activation characterized by increases in circulating pro-inflammatory Ly6Chi monocytes in ApoE
    Sprache Englisch
    Erscheinungsdatum 2021-08-04
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2836493-4
    ISSN 2056-3973
    ISSN 2056-3973
    DOI 10.1038/s41514-021-00071-w
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  7. Artikel ; Online: Impaired Luminal Control of Intestinal Macrophage Maturation in Patients With Ulcerative Colitis During Remission.

    Maasfeh, Lujain / Härtlova, Anetta / Isaksson, Stefan / Sundin, Johanna / Mavroudis, Georgios / Savolainen, Otto / Strid, Hans / Öhman, Lena / Magnusson, Maria K

    Cellular and molecular gastroenterology and hepatology

    2021  Band 12, Heft 4, Seite(n) 1415–1432

    Abstract: Background & aims: Intestinal macrophages adopt a hyporesponsive phenotype through education by local signals. Lack of proper macrophage maturation in patients with ulcerative colitis (UC) in remission may initiate gut inflammation. The aim, therefore, ... ...

    Abstract Background & aims: Intestinal macrophages adopt a hyporesponsive phenotype through education by local signals. Lack of proper macrophage maturation in patients with ulcerative colitis (UC) in remission may initiate gut inflammation. The aim, therefore, was to determine the effects of fecal luminal factors derived from healthy donors and UC patients in remission on macrophage phenotype and function.
    Methods: Fecal supernatants (FS) were extracted from fecal samples of healthy subjects and UC patients in remission. Monocytes were matured into macrophages in the presence of granulocyte-macrophage colony-stimulating factor without/with FS, stimulated with lipopolysaccharide, and macrophage phenotype and function were assessed. Fecal metabolomic profiles were analyzed by gas-chromatography/mass-spectrometry.
    Results: Fecal luminal factors derived from healthy donors were effective in down-regulating Toll-like receptor signaling, cytokine signaling, and antigen presentation in macrophages. Fecal luminal factors derived from UC patients in remission were less potent in inducing lipopolysaccharide hyporesponsiveness and modulating expression of genes involved in macrophage cytokine and Toll-like receptor signaling pathways. Although phagocytic and bactericidal abilities of macrophages were not affected by FS treatment, healthy FS-treated macrophages showed a greater ability to suppress cluster of differentiation 4
    Conclusions: Our data indicate that UC patients in remission lack luminal signals able to condition macrophages toward a hyporesponsive and tolerogenic phenotype, which may contribute to their persistent vulnerability to relapse.
    Mesh-Begriff(e) Biomarkers ; Case-Control Studies ; Colitis, Ulcerative/drug therapy ; Colitis, Ulcerative/etiology ; Colitis, Ulcerative/metabolism ; Colitis, Ulcerative/pathology ; Cytokines/metabolism ; Disease Management ; Disease Susceptibility ; Feces/chemistry ; Gene Expression Regulation ; Humans ; Immunophenotyping ; Inflammation Mediators ; Intestinal Mucosa/immunology ; Intestinal Mucosa/metabolism ; Intestinal Mucosa/pathology ; Lipopolysaccharides/immunology ; Macrophage Activation ; Macrophages/immunology ; Macrophages/metabolism ; Macrophages/pathology ; Metabolome ; Metabolomics/methods ; Monocytes/immunology ; Monocytes/metabolism ; Phagocytosis ; Signal Transduction ; Toll-Like Receptors/metabolism
    Chemische Substanzen Biomarkers ; Cytokines ; Inflammation Mediators ; Lipopolysaccharides ; Toll-Like Receptors
    Sprache Englisch
    Erscheinungsdatum 2021-06-12
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2819778-1
    ISSN 2352-345X ; 2352-345X
    ISSN (online) 2352-345X
    ISSN 2352-345X
    DOI 10.1016/j.jcmgh.2021.06.004
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel ; Online: Assessing the Phagosome Proteome by Quantitative Mass Spectrometry.

    Peltier, Julien / Härtlova, Anetta / Trost, Matthias

    Methods in molecular biology (Clifton, N.J.)

    2016  Band 1519, Seite(n) 249–263

    Abstract: Phagocytosis is the process that engulfs particles in vesicles called phagosomes that are trafficked through a series of maturation steps, culminating in the destruction of the internalized cargo. Because phagosomes are in direct contact with the ... ...

    Abstract Phagocytosis is the process that engulfs particles in vesicles called phagosomes that are trafficked through a series of maturation steps, culminating in the destruction of the internalized cargo. Because phagosomes are in direct contact with the particle and undergo constant fusion and fission events with other organelles, characterization of the phagosomal proteome is a powerful tool to understand mechanisms controlling innate immunity as well as vesicle trafficking. The ability to isolate highly pure phagosomes through the use of latex beads led to an extensive use of proteomics to study phagosomes under different stimuli. Thousands of different proteins have been identified and quantified, revealing new properties and shedding new light on the dynamics and composition of maturing phagosomes and innate immunity mechanisms. In this chapter, we describe how quantitative-based proteomic methods such as label-free, dimethyl labeling or Tandem Mass Tag (TMT) labeling can be applied for the characterization of protein composition and translocation during maturation of phagosomes in macrophages.
    Mesh-Begriff(e) Animals ; Humans ; Mass Spectrometry/methods ; Mice ; Phagosomes/metabolism ; Proteome/metabolism ; Proteomics ; Quality Control ; Staining and Labeling ; Statistics as Topic
    Chemische Substanzen Proteome
    Sprache Englisch
    Erscheinungsdatum 2016-11-04
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-4939-6581-6_17
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  9. Artikel ; Online: MEFV and NLRP3 Inflammasome Expression Is Attributed to Immature Macrophages and Correlates with Serum Inflammatory Proteins in Crohn´s Disease Patients.

    Gorreja, Frida / Caër, Charles / Rush, Stephen T A / Forsskål, Sophia K / Härtlova, Anetta / Magnusson, Maria K / Bexe Lindskog, Elinor / Börjesson, Lars G / Block, Mattias / Wick, Mary Jo

    Inflammation

    2022  Band 45, Heft 4, Seite(n) 1631–1650

    Abstract: Inflammasomes are intracellular protein complexes whose activation results in proinflammatory cytokines. Inflammasomes are implicated in Crohn´s disease (CD) pathogenesis, yet the contribution of inflammasomes in intestinal epithelial cells (IECs) versus ...

    Abstract Inflammasomes are intracellular protein complexes whose activation results in proinflammatory cytokines. Inflammasomes are implicated in Crohn´s disease (CD) pathogenesis, yet the contribution of inflammasomes in intestinal epithelial cells (IECs) versus lamina propria (LP) macrophages is poorly understood. Whether inflammasome expression in intestinal tissue reflects the serum inflammatory protein profile of patients is also not known. We aimed to determine the intestinal cell types where inflammasome expression is increased in CD and if they correlate with the serum protein profile. RT-PCR and NanoString nCounter technology were used to characterize inflammasome gene expression in CD patients and controls. The mucosa, LP and IEC cell fractions and FACS-sorted cells were analyzed. Proximity extension assay with a 92-protein panel was used to determine the serum inflammatory protein profile. Compositional analysis was used to correlate ileum inflammasome gene expression with intestinal mononuclear phagocyte populations. We show that NLRP3 and MEFV inflammasome sensors and downstream effector expression including IL-1β are increased in inflamed mucosa of IBD patients and correlate with disease activity. Inflammasome gene expression increased with the abundance of immature intestinal macrophages, and increased IL-1β released by CD LP cells correlated with immature macrophage frequency. Inflammasome gene expression was also increased in circulating monocytes, the precursors of immature intestinal macrophages. Finally, the serum inflammatory profile of CD patients correlates with ileal expression of genes related to NLRP3 and MEFV inflammasomes. Overall, we show that MEFV and NLRP3 inflammasome expression in CD intestine is attributed to the accumulation of immature macrophages and correlates with serum inflammatory proteins.
    Mesh-Begriff(e) Blood Proteins/metabolism ; Crohn Disease/metabolism ; Humans ; Inflammasomes/metabolism ; Interleukin-1beta/metabolism ; Macrophages/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Pyrin/genetics ; Pyrin/metabolism
    Chemische Substanzen Blood Proteins ; Inflammasomes ; Interleukin-1beta ; MEFV protein, human ; NLR Family, Pyrin Domain-Containing 3 Protein ; NLRP3 protein, human ; Pyrin
    Sprache Englisch
    Erscheinungsdatum 2022-02-21
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 434408-x
    ISSN 1573-2576 ; 0360-3997
    ISSN (online) 1573-2576
    ISSN 0360-3997
    DOI 10.1007/s10753-022-01647-8
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  10. Artikel ; Online: The E3 ubiquitin ligase RNF115 regulates phagosome maturation and host response to bacterial infection.

    Bilkei-Gorzo, Orsolya / Heunis, Tiaan / Marín-Rubio, José Luis / Cianfanelli, Francesca Romana / Raymond, Benjamin Bernard Armando / Inns, Joseph / Fabrikova, Daniela / Peltier, Julien / Oakley, Fiona / Schmid, Ralf / Härtlova, Anetta / Trost, Matthias

    The EMBO journal

    2022  Band 41, Heft 23, Seite(n) e108970

    Abstract: Phagocytosis is a key process in innate immunity and homeostasis. After particle uptake, newly formed phagosomes mature by acquisition of endolysosomal enzymes. Macrophage activation by interferon gamma (IFN-γ) increases microbicidal activity, but delays ...

    Abstract Phagocytosis is a key process in innate immunity and homeostasis. After particle uptake, newly formed phagosomes mature by acquisition of endolysosomal enzymes. Macrophage activation by interferon gamma (IFN-γ) increases microbicidal activity, but delays phagosomal maturation by an unknown mechanism. Using quantitative proteomics, we show that phagosomal proteins harbour high levels of typical and atypical ubiquitin chain types. Moreover, phagosomal ubiquitylation of vesicle trafficking proteins is substantially enhanced upon IFN-γ activation of macrophages, suggesting a role in regulating phagosomal functions. We identified the E3 ubiquitin ligase RNF115, which is enriched on phagosomes of IFN-γ activated macrophages, as an important regulator of phagosomal maturation. Loss of RNF115 protein or ligase activity enhanced phagosomal maturation and increased cytokine responses to bacterial infection, suggesting that both innate immune signalling from the phagosome and phagolysosomal trafficking are controlled through ubiquitylation. RNF115 knock-out mice show less tissue damage in response to S. aureus infection, indicating a role of RNF115 in inflammatory responses in vivo. In conclusion, RNF115 and phagosomal ubiquitylation are important regulators of innate immune functions during bacterial infections.
    Mesh-Begriff(e) Animals ; Mice ; Bacterial Infections/metabolism ; Interferon-gamma/metabolism ; Phagocytosis ; Phagosomes/metabolism ; Staphylococcus aureus ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism
    Chemische Substanzen Interferon-gamma (82115-62-6) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Rnf115 protein, mouse (EC 2.3.2.27)
    Sprache Englisch
    Erscheinungsdatum 2022-10-25
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 586044-1
    ISSN 1460-2075 ; 0261-4189
    ISSN (online) 1460-2075
    ISSN 0261-4189
    DOI 10.15252/embj.2021108970
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