TNFR1-activated NF-κB signal transduction: regulation by the ubiquitin/proteasome system

The Tumor Necrosis Factor Receptor-1 (TNFR1) is a central regulator of inflammation, cell death, and cellular proliferation. As such, alterations in TNFR1 signaling are associated with numerous diseases ranging from autoimmune syndromes to cancer. Understanding the regulation of TNFR1 signaling is therefore of considerable importance. The transduction of signaling events in the TNFR1 pathway - from ligand binding through transcriptional regulation - is regulated at nearly every step by post-translational modifications, including ubiquitination. In this review both endogenous and pharmacologic inhibitors of TNFR1 signaling, and how these impact the ubiquitin system, will be discussed.