Monoubiquitination as a Novel Proteasomal Degradation Signal: Mechanistic and Biomedical Implications

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講演要旨

The ‘canonical’ hallmark of the proteasomal recognition signal is a polyubiquitin chain linked internally via Lys48 and anchored to an ε-amino group of a Lys residue in the substrate. Recently, it has become clear that the signal is far more complex and diverse, and contains information from both ubiquitin and the substrate. Thus, the proteasome can recognize substrates modified by a single (monoubiquitination) or several single (multiple monoubiquitinations) ubiquitins, short chains (oligoubiquitination), and polyubiquitin chains assembled via other Lys residues. Chains anchored to internal Cys, Ser, and Thr, or to the N-terminal residue of the substrate have also been identified. It has also become clear that mere conjugation of ubiquitin to the substrate is not always sufficient to render it susceptible for degradation: substrate’s features such as an unstructured tail are important too, probably to facilitate their entry into the 20S catalytic core.

We have recently shown that the length of the substrate is one important characteristic that determines whether it will undergo mono- or polyubiquitination (Shabek et al., Mol Cell, 2012). We have also shown that the p105 NF-B precursor is processed to the p50 active subunit of the transcriptional regulator following multiple monoubiquitination (Kravtsova-Ivantsiv et al., Mol Cell 2009), and that this process is probably mediated by the KPC1 ubiquitin ligase (Kravtsova-Ivantsiv et al., CELL, 2015). Interestingly, this activity of KPC1 has a strong tumor suppressing effect. This new ‘canon’ has raised many question. For example, which substrates are degraded following mono-, oligo- or polyubiquitination, and what characterizes them? What is the role of the polyubiquitin chain? Does it increase the affinity of the substrate to the proteasome, thus increasing the processivity of proteolysis, or does it also alter inherent properties of the conjugated substrate? What limits the extent of ubiquitination (mono-, and short vs. long chains?), and are there specific ligases, E3s, involved in mono- vs. oligo- or polyubiquitination? Is the specific anchoring site of ubiquitin to the target protein important for its efficient degradation? And then, what is the mechanism that underlies the tumor suppressive activity of KPC1. In a recent proteomic screen we carried out, where we replaced all cellular WT ubiquitin with a ubiquitin species that cannot be polymerized, we found numerous proteins that are degraded following mono-ubiquitination rather than poly-ubiquitination. Interestingly, these proteins have unique characteristics - they are relatively small in their molecular mass and are of lesser structural order (Braten et al., PNAS, 2016). As for the tumor suppressive mechanism, we discovered that the newly formed putative transcription factor, the p50p50 homodimer induces – by an as yet unknown mechanism – recruitment of the immune system to the tumor, which possibly acts to suppress its growth.