Seminar

Ubiquitin networks in regulation of inflammation and autophagy

IVAN DIKIC, PhD

An increasing number of distinct functions have been assigned to different types of ubiquitin modifications (mono ubiquitin versus ubiquitin chains). In these processes Ub acts as a signalling component able to trigger molecular events in cells. Structural studies have revealed significant differences between ubiquitin chains of Lys48, Lys63 and linear linkages. We have recently shown that the UBAN domain of NF-κB essential modulator (NEMO) binds specifically to linear Ub chains and that this step is essential for NF-κB activation. These findings explain the detrimental effect of NEMO mutations in patients suffering from X-linked ectodermal dysplasia and immunodeficiency. More recently, we have identified novel components of the linear ubiquitin-dependent pathways that control the NF-κB and apoptotic pathways downstream of TNF receptors.

Removal of harmful protein aggregates, damaged organelles and microbes is mediated by autophagy, a process by which the cell sequesters cytosolic cargo and delivers it for degradation by the lysosome. The involvement of ubiquitin in selective autophagy is becoming more evident: autophagic clearance of protein aggregates requires specific autophagy receptors. Identification of p62/SQSTM1 and NBR1 as autophagy receptors, which simultaneously bind both ubiquitin and autophagy-specific ubiquitin-like modifiers, LC3/GABARAP, has provided a molecular link between ubiquitination and autophagy. The molecular details of selective autophagy suitable for clearance of various cargoes, ranging from ubiquitinated protein aggregates to membrane-bound organelles and microbes will be discussed.