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MPS |
allgemeines |
Mononukleär-phagozytäres System,
Monozyten-Makrophagen-System. |
Teil der
angeborenen Immunabwehr |
| Einordnung |
Zellen, die zur Phagozytose und
Speicherung befähigt sind. |
Das retikulohistiozytäre System
(RHS) ist eine Teilmenge des MPS. |
| Funktion |
Phagozytose von Bakterien, Zelltrümmern. |
Antigenpräsentierende Zellen (APC). |
| Zellen |
Makrophagen,
Monozyten, Retikulumzellen, Epitheloidzellen,
Kupffer-Sternzellen, Langerhans-Zellen, Osteoklasten, Hofbauer-Zellen,
Mikrogliazellen, Mesangiumzellen |
| Pathologie |
Systemische und lokale Potenzierung chronisch entzündlicher Erkrankungen. |
| TLR |
Toll-like Receptors. |
Rezeptoren der angeborenen Immunabwehr (PRR). |
| STING |
cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING
Detection of cytoplasmic DNA represents one of the most fundamental mechanisms of the innate immune system to sense the presence of microbial pathogens1.
Moreover, erroneous detection of endogenous DNA by the same sensing mechanisms has an important pathophysiological role in certain sterile inflammatory conditions
endoplasmic-reticulum-resident protein STING is critically required for the initiation of type I interferon signalling upon detection of cytosolic DNA of both exogenous and endogenous origin
Next to its pivotal role in DNA sensing, STING also serves as a direct receptor for the detection of cyclic dinucleotides, which function as second messenger molecules in bacteria
DNA recognition, however, is triggered in an indirect fashion that depends on a recently characterized cytoplasmic nucleotidyl transferase, termed cGAMP synthase (cGAS), which upon interaction
with DNA synthesizes a dinucleotide molecule that in turn binds to and activates STING
We here show in vivo and in vitro that the cGAS-catalysed reaction product is distinct from previously characterized cyclic dinucleotides. Using a combinatorial approach based on mass spectrometry,
enzymatic digestion, NMR analysis and chemical synthesis we demonstrate that cGAS produces a cyclic GMP-AMP dinucleotide, which is comprised of a 2'-5' and a 3'-5' phosphodiester linkage >Gp(2'-5')Ap(3'-5')>.
We found that the presence of this 2'-5' linkage was required to exert potent activation of human STING. Moreover, we show that cGAS first catalyses the
synthesis of a linear 2'-5'-linked dinucleotide, which is then subject to
cGAS-dependent cyclization in a second step through a 3'-5' phosphodiester
linkage. This 13-membered ring structure defines a novel class of second
messenger molecules, extending the family of 2'-5'-linked antiviral
biomolecules. |
Teil von |
Zellen des Immunsystems |
Immunologie |
Blut, Knochenmark |
| Quellen |
1.) Uderhardt S, et al.:
12/15-Lipoxygenase Orchestrates the Clearance of Apoptotic Cells and Maintains
Immunologic Tolerance.
Immunity Published online: April 12, 2012
2.) Nairz M, et al.:
Nitric oxide-mediated regulation of ferroportin-1 controls macrophage iron
homeostasis and immune function in Salmonella infection.
JEM 210(2013):855-873, doi: 10.1084/jem.20121946; 2013
3.) Ablasser A, et al.:
cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING.
Nature (2013)
doi:10.1038/nature12306
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