Inflammation is a double-edged sword: it is necessary to fight infection, but if uncontrolled is associated with serious pathologies such as rheumatoid arthritis, inflammatory bowel disease or liver cancer. That is why the proinflammatory signal transduction is switched off when cells have no contact with the activating molecules. In the paper published in Science Signaling Mamińska and coworkers propose a new mechanism used by the cells to prevent uncontrolled inflammatory signaling.
The study shows that the key proinflammatory signaling pathway called NF-κB is activated without a specific signal when the endosomal sorting system is blocked. During endocytosis, extracellular cargo is internalized into a cell with fragments of the plasma membrane, forming cargo-loaded vesicles. An example of such cargo are proinflammatory ligands along with their specific receptors. The internalized material is then sorted towards degradation or recycled back to the plasma membrane. The degradation-directed sorting is orchestrated by the set of multiprotein complexes called ESCRTs (Endosomal Sorting Complexes Required for Transport). Endocytic degradation has been long recognized as a mechanism to remove the receptors from the plasma membrane after they get associated with their specific ligands, and in this way turn the signal off. In the published work Mamińska et al. show that receptors activating the NF-κB pathway such as LTβR or TNFR1 get stuck on early endosomes, even in the absence of ligands, when several ESCRT components are removed from the cell (scheme, right panel). Solely decreasing the amount of ESCRT components Tsg101, Vps28, UBAP1 (ESCRT-I) or CHMP4B (ESCRT-III) leads to dramatic consequences. The receptors uncontrollably accumulate on the endosomes, associate with their signaling partners, and activate the transduction cascade that ultimately leads to expression of the NF-κB dependent genes. The full-blown inflammatory response is activated, although there is no exogenous ligand.
These results suggest that active and fully functional ESCRT machinery is necessary to inhibit basal NF-κB signaling by constitutive sorting of receptors towards degradation (scheme, left panel) and in this way prevent unspecific inflammation. It also shows that NF-κB-inducing receptors are able to signal from endosomes, even without stimulation. The results originally observed and elaborated in cultured human cells in the Laboratory of Cell Biology led by Marta Miączyńska were confirmed in model organisms: the zebrafish and the fruitfly thanks to the coordinated international collaboration, including groups from Geneva, Nice, Lausanne, Warsaw and Oslo.
This study was primarily supported by a grant from Switzerland through the Swiss Contribution to the enlarged European Union (Polish-Swiss Research Programme project PSPB-094/2010), awarded to Marta Miączyńska and Marcos González-Gaitán.
Original Publication:
Agnieszka Mamińska, Anna Bartosik, Magdalena Banach-Orłowska, Iwona Pilecka, Kamil Jastrzębski, Daria Zdżalik-Bielecka, Irinka Castanon, Morgane Poulain, Claudine Neyen, Lidia Wolińska-Nizioł, Anna Toruń, Ewelina Szymańska, Agata Kowalczyk, Katarzyna Piwocka, Anne Simonsen, Harald Stenmark, Maximilian Fürthauer, Marcos González-Gaitán, and Marta Miaczynska.
ESCRT proteins restrict constitutive NF-κB signaling by trafficking cytokine receptors.
2016. Science Signaling doi: 10.1126/scisignal.aad0848
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