Dikic Lab

Molecular Signaling Group

 

About

Head: Prof. Ivan Dikic

Research in the Dikic group is centered around the two major cellular quality control pathways: the ubiquitin system and autophagy. As such they provide protection against rapid aging and various human diseases and are involved in almost all cellular signaling processes.
Ubiquitin (Ub) is a highly conserved 76-amino acid polypeptide that is covalently attached to target proteins through a universally conserved three-step enzymatic process involving ubiquitin activating (E1), ubiquitin conjugating (E2) and ubiquitin ligating (E3) enzymes. Proteins can be modified by one (mono-ubiquitination) or several (multi-ubiquitination) single ubiquitin molecule(s). In addition, polyubiquitination of substrates occurs by the conjugation of ubiquitin proteins through one of its 7 lysine residues (K6, K11, K27, K29, K33, K48 and 63) or the N-terminal Methionine (M1) forming ubiquitin chains. Each type of Ub linkage is specifically recognised by specialised ubiquitin binding domains (UBD). To date, 20 families of UBDs have been characterized according to their specificity for Ub linkages (figure 1).
Given its high versatility, ubiquitination of proteins impacts almost all cellular pathways such as DNA repair, the immune response, endocytosis, autophagy, signaling and protein degradation (Hershko et al., 2000)

About Dikic Fig1

Figure 1: Ubiquitin binding domains recognise specific Ub linkages and have specialised functions. From Rajalingam and Dikic, 2016

Autophagy is a lysosome-mediated intracellular degradation pathway, which involves the formation of double-membrane vesicles (autophagosomes) that sequester portions of the cytoplasm or organelles and eventually fuse with the lysosome, where their cargo is degraded (figure 2). At first, autophagy was assumed to be a non-selective process to generate essential nutrients and building blocks required during cell starvation. However, during the last years, it became clear that autophagy is a tightly regulated, selective process that enables the specific degradation of damaged organelles, such as mitochondria (“mitophagy”), endoplasmic reticulum (“ER-phagy”) or invaded pathogens (“xenophagy”), maintaining cellular homeostasis.

Dikic Fig2

Figure 2: Overview of selective autophagy. From (Stolz et al., 2014)