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Maminska A.,International Institute of Molecular AndCell Biology | Bartosik A.,International Institute of Molecular AndCell Biology | Banach-Orlowska M.,International Institute of Molecular AndCell Biology | Pilecka I.,International Institute of Molecular AndCell Biology | And 15 more authors.
Science Signaling | Year: 2016

Because signaling mediated by the transcription factor nuclear factor kB (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 constitutiveNF-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 b receptor (LTbR) and tumor necrosis factor receptor 1 (TNFR1).Upon depletion ofESCRTsubunits, both receptors becameconcentrated on and signaled from endosomes. Endosomal accumulation of LTbR 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.

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