Dataset Information

A High-Content RNAi Screen Identifies Ubiquitin Modifiers That Regulate TNF-Dependent Nuclear Accumulation of NF-κB.

ABSTRACT: The mammalian tumor necrosis factor (TNF) cytokine is a central mediator of inflammatory events. Recent studies revealed a number of complex and sophisticated interactions between the TNF pathway and the enzymatic activities encoded by ubiquitin ligases and deubiquitylation enzymes. However, very little is known about the identity of the ubiquitin pathway members that control the extent of ubiquitylation in TNF responses. To address this deficit, we conducted an unbiased, high-content screen of the human ubiquitin pathway for gene products that control defining features of the cellular response to TNF. In particular, we sought to identify ubiquitin modifying enzymes that alter the ability of TNF to regulate the nuclear accumulation of nuclear factor kappa B. In this screen, we identified and validated several novel regulators of the TNF pathway. We believe these regulators constitute potential targets for pharmacological interventions that manipulate TNF-dependent inflammation.

SUBMITTER: Fraser B

PROVIDER: S-EPMC4094887 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

A High-Content RNAi Screen Identifies Ubiquitin Modifiers That Regulate TNF-Dependent Nuclear Accumulation of NF-κB.

Fraser Brittany B Maranchuk Robert A RA Foley Edan E

Frontiers in immunology 20140714

The mammalian tumor necrosis factor (TNF) cytokine is a central mediator of inflammatory events. Recent studies revealed a number of complex and sophisticated interactions between the TNF pathway and the enzymatic activities encoded by ubiquitin ligases and deubiquitylation enzymes. However, very little is known about the identity of the ubiquitin pathway members that control the extent of ubiquitylation in TNF responses. To address this deficit, we conducted an unbiased, high-content screen of ...[more]

PMID: 25071782

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Project description:Tumor necrosis factor (TNF) is a pleiotropic cytokine whose primary physiological function involves coordinating inflammatory and adaptive immune responses. However, uncontrolled TNF signaling causes aberrant inflammation and has been implicated in several human ailments. Therefore, an understanding of the molecular mechanisms underlying dynamical and gene controls of TNF signaling bear significance for human health. As such, TNF engages the canonical nuclear factor kappa B (NF-κB) pathway to activate RelA:p50 heterodimers, which induce expression of specific immune response genes. Brief and chronic TNF stimulation produces transient and long-lasting NF-κB activities, respectively. Negative feedback regulators of the canonical pathway, including IκBα, are thought to ensure transient RelA:p50 responses to short-lived TNF signals. The non-canonical NF-κB pathway mediates RelB activity during immune differentiation involving p100. We uncovered an unexpected role of p100 in TNF signaling. Brief TNF stimulation of p100-deficient cells triggered an additional late NF-κB activity consisting of RelB:p50 heterodimers, which modified the TNF-induced gene-expression program. In p100-deficient cells subjected to brief TNF stimulation, RelB:p50 not only sustained the expression of a subset of RelA-target immune response genes but also activated additional genes that were not normally induced by TNF in WT mouse embryonic fibroblasts (MEFs) and were related to immune differentiation and metabolic processes. Despite this RelB-mediated distinct gene control, however, RelA and RelB bound to mostly overlapping chromatin sites in p100-deficient cells. Repeated TNF pulses strengthened this RelB:p50 activity, which was supported by NF-κB-driven RelB synthesis. Finally, brief TNF stimulation elicited late-acting expressions of NF-κB target pro-survival genes in p100-deficient myeloma cells. In sum, our study suggests that the immune-differentiation regulator p100 enforces specificity of TNF signaling and that varied p100 levels may provide for modifying TNF responses in diverse physiological and pathological settings.

Dataset Information

A High-Content RNAi Screen Identifies Ubiquitin Modifiers That Regulate TNF-Dependent Nuclear Accumulation of NF-κB.

Publications

A High-Content RNAi Screen Identifies Ubiquitin Modifiers That Regulate TNF-Dependent Nuclear Accumulation of NF-κB.

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