E3 UBIQUITIN LIGASES AND UBIQUITIN SIGNALING
Ubiquitination is a highly versatile posttranslational modification regulating fundamental cellular processes, such as protein and organelle turnover, protein trafficking, DNA repair, endocytosis, signaling pathways, and cell cycle progression. Ubiquitination is accomplished by the coordinated action of three enzymes, an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase (Figure 1). Ubiquitin can be attached to substrate proteins as a single moiety or in form of polymeric chains. Reminiscent of a code, the various ubiquitin modifications adopt distinct conformations and serve different cellular functions (Figure 2).
Figure 1: Mechanism of ubiquitination mediated by an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase. Three classes of E3 ubiquitin ligases have been identified: RING ligases (left), RBR (RING-between-RING) ligases (middle), and HECT ligases (right), which show differences in the mechanism of ubiquitin transfer to the substrate. ©TRENDS in Cell Biology
Figure 2: The ubiquitin code. Within polyubiquitin chains, ubiquitin can form eight different linkage types, using one of the seven intrinsic lysine (K) residues or methionine (M) at position 1. Each linkage type has a distinct three-dimensional topology which results in specific interactions and underlies the regulation of various biological functions. ©Lena Berlemann
A major focus of our interest is the E3 ubiquitin ligase Parkin, which is associated with autosomal recessive Parkinson's disease (PD). Our previous work has established that Parkin plays an important role in the cellular stress response and prevents neuronal cell death in various stress paradigms. We could demonstrate that Parkin is recruited to the linear ubiquitin chain assembly complex (LUBAC) in response to cellular stress, resulting in the activation of NF-κB signaling (Figure 3). We are currently analyzing the regulation of this pathway and its impact on neuronal viability. Moreover, we are studying whether this pathway mediates a crosstalk between neuroinflammation and neurodegeneration.
