Aaron Ciechanover, MD, DSc
Distinguished Technion Professor
MD, 1974- Hebrew University, Israel
DSc, 1982 -Technion, Israel
Involvement of the ubiqutin proteolytic system in activation of NF-κB and tumor suppression
Modification of proteins by ubiquitin and ubiquitin-like proteins affects their stability (Figure 1), function or cellular localization, and is involved in regulation of most cellular processes, including transcription, differentiation, cell cycle and division, and maintenance of cellular quality control. As a result, aberrations in the ubiquitin system underlie the mechanisms of many diseases, malignancies and neurodegenerative disorders among them (Figure 2). The capability of modification by the same protein - ubiquitin - to control a broad array of functions is due not only to its numerous cellular targets, but also to the evolution of multiple signals whereby different polymers of ubiquitin and ubiquitin-like proteins serve different functions. We are studying the different signals that target proteins to proteasomal degradation, limited processing, and autophagy, in order to understand how the fate of a target substrate is determined by the unique nature of its modification. One specific subject is the generation of active NF-κB from an inactive longer precursor – a process that requires a unique modification by several single moieties of ubiquitin. We found that the ubiquitin ligase KPC1 involved in this process displays strong tumor suppressive characteristics (Figure 3), which contrast with the known attributes of the NF-kB factor that support promotion of tumors by suppressing cell death and promoting cell division. Because of these unique characteristics, NF-kB is considered an ideal target for the development of novel anti-cancer therapies. Another important subject of research in the laboratory is how the ubiquitin system - which is a destructive system - destroys itself, or how its components are degraded. We have shown that like any other proteins, the components of the system are subject to degradation either via suicide or via autophagy.
Kravtsova-Ivantsiv Y, Shomer I, Cohen-Kaplan V, Snijder B, Superti-Furga G, Gonen H, Sommer T, Ziv T, Admon A, Naroditsky I, Jbara M, Brik A, Pikarsky E, Kwon YT, Doweck I, and Ciechanover A. 2015. KPC1-mediated ubiquitination and proteasomal processing of NF-κB p105 to p50 restricts tumor growth. Cell 161, 333-347.
Ciechanover A. 2015. The unraveling of the ubiquitin system. Nature Rev. Mol. Cell. Biol. 16, 322-324.
Buchsbaum S, Bercovich B, and Ciechanover A. 2012. FAT10 is a proteasomal degradation signal which is itself regulated by ubiquitination. Mol. Biol. Cell 23, 225-232.
Shabek N, Herman-Bachinsky Y, Buchsbaum S, Lewinson O, Haj-Yahya M, Hejjaoui M, Lashuel HA, Sommer T, Brik A, and Ciechanover A. 2012. The size of the proteasomal substrate determines whether its degradation will be mediated by mono- or polyubiquitylation. Mol. Cell 48, 87-97. Reviewed by F1000 - http://f1000.com/717953569#comments Reviewed by Nature Reviews in Cell and Molecular Biology - http://www.nature.com/nrm/journal/v13/n10/full/nrm3445.html?WT.ec_id=NRM-201210
Kravtsova-Ivantsiv Y, Cohen S, and Ciechanover A. 2009. Modification by single ubiquitin moieties rather than polyubiquitination is sufficient for proteasomal processing of the p105 NF-κB Precursor. Mol. Cell 33, 496-504.
Figure 1: The ubiquitin-proteasome proteolytic system.
Degradation of a protein by the ubiquitin-proteasome system involves two successive steps: (i) multi-step and multi-enzyme (E1, E2 and E3) activation and conjugation of multiple ubiquitin moieties to the target substrate to generate the polyubiquitin proteasomal proteolytic signal (steps 1-4); and (ii) degradation of the ubiquitin-tagged protein by the 26S proteasome (steps 5, 6). Finally, free and reusable ubiquitin is recycled following the activity of deubiquitinating (DUBs) enzymes (step 7)
Figure 2: Aberrations in the ubiquitin-proteasome system and pathogenesis of human diseases.
Normal degradation of cellular proteins maintains them at a steady state level (upper and lower right side). When degradation is accelerated due to an increase in the level of an E3, the steady state level of the protein decreases (upper left side). For example, accelerated degradation of the tumor suppressor p53 driven by the human papilloma virus (HPV) oncogene E6 exposes the cells of the cervical uterine epithelium to malignant transformation. In another case, mutation in a ubiquitin ligase or in the substrate's recognition motif results in decreased degradation and accumulation of the target substrate. Thus, decreased degradation of β-Catenin as a result of a mutation in its phosphorylation site leads to accumulation, excessive transcriptional activity and malignant transformation of the colorectal epithelium.
Figure 3: The Ubiquitin Ligase KPC1 is involved in processing of the p105 NF-kB precursor to p50 and is a strong tumor suppressor.
(A) Growth rates and weights of tumor xenografts in mice derived from U87-MG Glioblastoma cells expressing an empty vector (V0), KPC1, p50 and mutant, inactive KPC1. (B) Tumors derived from U87-MG cells 3 weeks after inoculation. (C) Immunohistochemical staining of human tumors derived from head and neck carcinomas and stained for KPC1 and nuclear p50. In the normal tissue (left panels) the staining strong. The staining is weaker in the malignant tissues (two middle panels). Whenever there is no KPC, we also do not see nuclear p50 (right panels).