Novel strategies to target the ubiquitin proteasome system in multiple myeloma

Abstract

Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of plasma cells in the bone marrow (BM). The success of the proteasome inhibitor bortezomib in the treatment of MM highlights the importance of the ubiquitin proteasome system (UPS) in this particular cancer. Despite the prolonged survival of MM patients, a significant amount of patients relapse or become resistant to therapy. This underlines the importance of the development and investigation of novel targets to improve MM therapy. The UPS plays an important role in different cellular processes by targeted destruction of proteins. The ubiquitination process consists of enzymes that transfer ubiquitin to proteins targeting them for proteasomal degradation. An emerging and promising approach is to target more disease specific components of the UPS to reduce side effects and overcome resistance. In this review, we will focus on different components of the UPS such as the ubiquitin activating enzyme E1, the ubiquitin conjugating enzyme E2, the E3 ubiquitin ligases, the deubiquitinating enzymes (DUBs) and the proteasome. We will discuss their role in MM and the implications in drug discovery for the treatment of MM.

Keywords: multiple myeloma; ubiquitin proteasome system.

Figure 1. different forms of ubiquitin modification

A. Ubiquitin is composed of 76 amino acids and contains seven lysine residues on which other ubiquitin molecules can be conjugated. B. A single ubiquitin is linked to a lysine (K) residue on the protein during mono-ubiquitination. Mono-ubiquitination is involved in endocytosis, DNA repair, histon regulation and protein transport. Multi-ubiquitination is obtained when multiple single ubiquitins are linked to different lysine residues on the protein and is implicated in endocytosis. However poly-ubiquitination is obtained when a poly-ubiquitin chain is linked to the protein. Poly-ubiquitin chains formed on lysine 48 (K48) of ubiquitin have a well-known role in targeted protein degradation by the 26S proteasome, whereas poly-ubiquitin chains formed through lysine 63 (K63) are involved in DNA repair and endocytosis.

Figure 2. illustration of the ubiquitin proteasome system (UPS)

The ubiquitin (Ub) is first activated by E1 in an ATP-dependent manner. The activated ubiquitin is then transferred to E2. E3 forms a complex with the target protein (or substrate) and recruits the E2-ubiquitin complex. The activated ubiquitin is then transferred from E2 to the target protein. This ubiquitination process can be reversed by deubiquitinating enzymes (DUBs). Finally, the ubiquitinated target gets recognized and degraded by the 26S proteasome. Several compounds targeting E1, E2, E3, DUBs and the proteasome have been studied, from which some of them are currently approved for the treatment of MM, while others are still under (pre)-clinical investigation.

Figure 3. composition of the proteasome

The proteasome consists of a 20S core particle and two 19S regulatory particles. The 20S core particle is composed of four rings creating a cylinder where the proteolysis occurs. The two α-rings are each formed by seven distinct α-subunits and serve as a docking domain for the 19S regulatory particle. The catalytic chamber is formed by the two inner β-rings, which are each formed by seven distinct β-subunits. The 19S regulatory particle binds a polyubiquitin chain and cleaves and recycles the ubiquitin. The substrate is then denaturated or unfolded and fed into the catalytic chamber where it is degraded into small peptides.