Ubiquitin-mediated regulation of TNFR1 signaling

Ubiquitin ligase enzymes promote substrate protein ubiquitination, a post-translational modification whereby the 76-amino acid protein ubiquitin is covalently bound to substrate proteins. Ubiquitination may target substrates for proteasomal degradation or regulate substrate function in a degradation-independent manner. Ubiquitination is reversible, and this is achieved by de-ubiquitinase enzymes [Jackson PK, Eldridge AG, Freed E, et al. The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases. Trends Cell Biol 2000;10(October (10)):429–39]. The first identified target of ubiquitination in the Tumor Necrosis Factor Receptor 1 (TNFR1) signaling cascade was Inhibitor of NF-κB (I-κB), which sequesters Nuclear Factors at κ-chain promoters in B-cells (NF-κB) transcription factors in the cytosol. Following TNF-α stimulation, I-κB is ubiquitinated and subsequently degraded by the proteasome, permitting NF-κB transcriptional activity [Glickman MH, Ciechanover A. The ubiquitin–proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 2002;82(April (2)):373–428]. Since this seminal finding, it is now evident that nearly every step of TNFR1 signaling is regulated by ubiquitination. In this review, we will summarize the ubiquitin/proteasome system and discuss the ubiquitin-mediated regulation of TNFR1 signaling.