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Sci Signal. 2016 Jan 19;9(411):ra8. doi: 10.1126/scisignal.aad0848.

ESCRT proteins restrict constitutive NF-κB signaling by trafficking cytokine receptors.

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International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
Department of Biochemistry, University of Geneva, 1211 Geneva, Switzerland.
Institut de Biologie Valrose, CNRS UMR 7277, INSERM 1091, University of Nice Sophia Antipolis, 06108 Nice, France.
École Polytechnique Fédérale de Lausanne (EPFL), Global Health Institute, 1015 Lausanne, Switzerland.
Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland.
Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway.
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway.
International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.


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.

[Indexed for MEDLINE]

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