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-kappaB (I-kappaB), which sequesters Nuclear Factors at kappa-chain promoters in B-cells (NF-kappaB) transcription factors in the cytosol. Following TNF-alpha stimulation, I-kappaB is ubiquitinated and subsequently degraded by the proteasome, permitting NF-kappaB 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.
Wertz
Ingrid E
IE
Department of Protein Engineering, Genentech, Inc., 1 DNA Way, M/S 40, South San Francisco, CA 94080, United States. ingrid@gene.com
Dixit
Vishva M
VM
D000818:Animals; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
D047888:Receptors, Tumor Necrosis Factor, Type I; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex