PUBLICATION
ESCRT proteins restrict constitutive NF-κB signaling by trafficking cytokine receptors
- Authors
- Mamińska, A., Bartosik, A., Banach-Orłowska, M., Pilecka, I., Jastrzębski, K., Zdżalik-Bielecka, D., Castanon, I., Poulain, M., Neyen, C., Wolińska-Nizioł, L., Toruń, A., Szymańska, E., Kowalczyk, A., Piwocka, K., Simonsen, A., Stenmark, H., Fürthauer, M., González-Gaitán, M., Miaczynska, M.
- ID
- ZDB-PUB-160121-4
- Date
- 2016
- Source
- Science signaling 9(411): ra8 (Journal)
- Registered Authors
- Fürthauer, Maximilian, Miaczynska, Marta, Poulain, Morgane
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Line, Tumor
- Endosomal Sorting Complexes Required for Transport/genetics
- Endosomal Sorting Complexes Required for Transport/metabolism*
- HEK293 Cells
- Humans
- NF-kappa B/genetics
- NF-kappa B/metabolism*
- Protein Transport/physiology
- Receptors, Cytokine/genetics
- Receptors, Cytokine/metabolism*
- Signal Transduction/physiology*
- Zebrafish/genetics
- Zebrafish/metabolism*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 26787452 Full text @ Sci. Signal.
Citation
Mamińska, A., Bartosik, A., Banach-Orłowska, M., Pilecka, I., Jastrzębski, K., Zdżalik-Bielecka, D., Castanon, I., Poulain, M., Neyen, C., Wolińska-Nizioł, L., Toruń, A., Szymańska, E., Kowalczyk, A., Piwocka, K., Simonsen, A., Stenmark, H., Fürthauer, M., González-Gaitán, M., Miaczynska, M. (2016) ESCRT proteins restrict constitutive NF-κB signaling by trafficking cytokine receptors. Science signaling. 9(411):ra8.
Abstract
Because signaling mediated by the transcription factor nuclear factor κB (NF-κB) is initiated by ligands and receptors that can undergo internalization, we investigated how endocytic trafficking regulated this key physiological pathway. We depleted all of the ESCRT (endosomal sorting complexes required for transport) subunits, which mediate receptor trafficking and degradation, and found that the components Tsg101, Vps28, UBAP1, and CHMP4B were essential to restrict constitutive NF-κB signaling in human embryonic kidney 293 cells. In the absence of exogenous cytokines, depletion of these proteins led to the activation of both canonical and noncanonical NF-κB signaling, as well as the induction of NF-κB-dependent transcriptional responses in cultured human cells, zebrafish embryos, and fat bodies in flies. These effects depended on cytokine receptors, such as the lymphotoxin β receptor (LTβR) and tumor necrosis factor receptor 1 (TNFR1). Upon depletion of ESCRT subunits, both receptors became concentrated on and signaled from endosomes. Endosomal accumulation of LTβR induced its ligand-independent oligomerization and signaling through the adaptors TNFR-associated factor 2 (TRAF2) and TRAF3. These data suggest that ESCRTs constitutively control the distribution of cytokine receptors in their ligand-free state to restrict their signaling, which may represent a general mechanism to prevent spurious activation of NF-κB.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping