Ubiquitin and Legionella: From bench to bedside

A new dawn beyond lysine ubiquitination

“…Deviating from Ub conjugation via its C-terminus, Legionella pneumophila effectors of the SidE family (SdeA, SdeB, SdeC and SidE) bypass the ubiquitination machinery entirely to conjugate an internal Ub residue to serine residues of host proteins through a phosphoribosyl linkage (Figure 1 and 2) 60 . Unexpectedly, the catalytic process requires nicotinamide adenine dinucleotide (NAD + ) and together with a mono ADP-ribosyltransferase (mART) domain, arginine 42 of Ub initially becomes ADPribosylated generating (ADPr-Ub) 20 .…”

“…Interestingly, tyrosine has also been shown to be a target of SidE effectors, raising the possibility that additional substrates of phosphoribosyl ubiquitination remain to be identified 64 . Illustrating the requirement for its sophisticated regulation, the Legionella enzymes DupA and DupB (Dups) are tasked with the removal of phosphoribosyl ubiquitination, which releases the substrate and PR-Ub 60 . These mediate their effect through a PDE domain similar to that found in SidE effectors but their opposing directionality is dictated by an enhanced affinity for Ub 22 .…”

Structural insights into ubiquitin chain cleavage byLegionellaovarian tumor deubiquitinases

“…Protein ubiquitination, a post-translational modification (PTM), regulates various cellular events in eukaryotes (Yau & Rape, 2016); thus, the disruption of the ubiquitination system leads to severe problems in humans, including cancer, Parkinson’s disease, and neurodegeneration (McNaught et al , 2001; Schmidt et al , 2021; Swatek & Komander, 2016; Tomaskovic et al , 2022). The canonical addition of ubiquitin is tightly regulated by the activating (E1), conjugating (E2), and ligating enzymes (E3) (Dikic & Schulman, 2022; Komander & Rape, 2012; Mukherjee & Dikic, 2022; Popovic et al , 2014; Swatek & Komander, 2016; Yau & Rape, 2016).…”

“…The canonical addition of ubiquitin is tightly regulated by the activating (E1), conjugating (E2), and ligating enzymes (E3) (Dikic & Schulman, 2022; Komander & Rape, 2012; Mukherjee & Dikic, 2022; Popovic et al , 2014; Swatek & Komander, 2016; Yau & Rape, 2016). Proteins can be ubiquitinated by monoubiquitin or polyubiquitin chains, and the linkages are formed via the seven lysine residues or the N-terminal methionine residue of ubiquitin (Komander & Rape, 2012; Mattiroli & Sixma, 2014; Swatek & Komander, 2016; Tomaskovic et al ., 2022). Different linkage types of ubiquitin polymers are involved in different cellular events, such as mitophagy and DNA damage repair (K6- and K27-linked chains), proteasomal degradation (K11- and K48-linked chains), innate immunity (K27-, K33-, and K63-linked chains), cell cycle regulation (K29-linked chains), protein trafficking (K33- and K63-linked chains), and the NF-kB signaling pathway (M1-linked chains) (Swatek & Komander, 2016).…”

Structural insights into ubiquitin chain cleavage byLegionellaovarian tumor deubiquitinases

“…Protein ubiquitination, a post-translational modification, regulates various cellular events in eukaryotes ( Yau & Rape, 2016 ); thus, the disruption of the ubiquitination system leads to severe problems in humans, including cancer, Parkinson’s disease, and neurodegeneration ( McNaught et al, 2001 ; Swatek & Komander, 2016 ; Schmidt et al, 2021 ; Tomaskovic et al, 2022 ). The canonical addition of ubiquitin is tightly regulated by the activating (E1), conjugating (E2), and ligating enzymes (E3) ( Komander & Rape, 2012 ; Popovic et al, 2014 ; Swatek & Komander, 2016 ; Yau & Rape, 2016 ; Dikic & Schulman, 2022 ; Mukherjee & Dikic, 2022 ).…”