Research ArticleCell Biology

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

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Sci. Signal.  19 Jan 2016:
Vol. 9, Issue 411, pp. ra8
DOI: 10.1126/scisignal.aad0848

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“ESCRT”ing receptors out of endosomes

Members of the nuclear factor κB (NF-κB) family of transcription factors are critical for cell survival, differentiation, inflammation, and immune responses. Many receptors that activate NF-κB are internalized and degraded, and receptor degradation depends on ESCRT (endosomal sorting complexes required for transport) complexes. By knocking down individual ESCRT components in cells, Mamińska et al. found that lack of ESCRT function enhanced NF-κB signaling as a result of increased clustering of ligand-free cytokine receptors at endosomes. Clustering at the endosomes activated these receptors, resulting in NF-κB–dependent gene expression. Thus, the ESCRT complex constitutively directs cytokine receptor trafficking to prevent endosomal accumulation and block spurious NF-κB activation.

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.

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