Ubiquitin proteasome system in immune regulation and therapeutics

Abstract

The ubiquitin proteasome system (UPS) is a proteolytic machinery for the degradation of protein substrates that are post-translationally conjugated with ubiquitin polymers through the enzymatic action of ubiquitin ligases, in a process termed ubiquitylation. Ubiquitylation of substrates precedes their proteolysis via proteasomes, a hierarchical feature of UPS. E3-ubiquitin ligases recruit protein substrates providing specificity for ubiquitylation. Innate and adaptive immune system networks are regulated by ubiquitylation and substrate degradation via E3-ligases/UPS. Deregulation of E3-ligases/UPS components in immune cells is involved in the development of lymphomas, neurodevelopmental abnormalities, and cancers. Targeting E3-ligases for therapeutic intervention provides opportunities to mitigate the unintended broad effects of 26S proteasome inhibition. Recently, bifunctional moieties such as PROTACs and molecular glues have been developed to re-purpose E3-ligases for targeted degradation of unwanted aberrant proteins, with a potential for clinical use. Here, we summarize the involvement of E3-ligases/UPS components in immune-related diseases with perspectives.

Figure 1. Ubiquitin conjugations and protein degradation via UPS.

Ubiquitylation of proteins takes place through the sequential action of three enzymes, E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin-protein ligase). Ubiquitin is activated by E1 in an ATP-dependent reaction followed by transfer to E2, which finally conjugates the activated ubiquitin to an internal lysine of the substrate bound to E3 or to the lysine of the growing polyubiquitin chain. E3s provide specificity in the ubiquitylation cascade by directly binding and recruiting substrates. Ubiquitin-conjugated substrate may be degraded by the proteasome (K48/K11 ubiquitin linkages) or deubiquitinated by the DUBs. BioRender software was used for making the figure.

Figure 2. Fate of various ubiquitin linkages.

K48- and K11-linked targets are the major substrates of proteasome-mediated degradation whereas autophagy substrates have mainly K63 linkage.

Figure 3. Targeting UPS components for therapeutics.

(a) Potential targets in the UPS for small molecule-mediated inhibition. Due to the direct binding of substrates to E3s, amongst all the potential UPS targets, E3 inhibition could be highly specific with minimum side effects (b) PROTAC-mediated targeted protein degradation. The PROTAC consists of an E3 binding region, a linker, and a substrate recruiting region and induces target protein degradation by drawing the substrate in proximity to the ligase. (c) Molecular glue-mediated target protein degradation. Molecular glue is a small molecule that interacts with both the ligase and the substrate and brings them in proximity to induce degradation. BioRender software was used for making the figure.