Modification of the host ubiquitome by bacterial enzymes

Abstract

Attachment of ubiquitin molecules to protein substrates is a reversible post-translational modification (PTM), which occurs ubiquitously in eukaryotic cells and controls most cellular processes. As a consequence, ubiquitination is an attractive target of pathogen-encoded virulence factors. Pathogenic bacteria have evolved multiple mechanisms to hijack the host's ubiquitin system to their advantage. In this review, we discuss the bacteria-encoded E3 ligases and deubiquitinases translocated to the host for an addition or removal of eukaryotic ubiquitin modification, effectively hijacking the host's ubiquitination processes. We review bacterial enzymes homologous to host proteins in sequence and functions, as well as enzymes with novel mechanisms in ubiquitination, which have significant structural differences in comparison to the mammalian E3 ligases. Finally, we will also discuss examples of molecular "counter-weapons" - eukaryotic proteins, which counteract pathogen-encoded E3 ligases. The many examples of the pathogen effector molecules that catalyze eukaryotic ubiquitin modification bring to light the intricate pathways involved in the pathogenesis of some of the most virulent bacterial infections with human pathogens. The role of these effector molecules remains an essential determinant of bacterial virulence in terms of infection, invasion, and replication. A comprehensive understanding of the mechanisms dictating the mimicry employed by bacterial pathogens is of vital importance in developing new strategies for therapeutic approaches.

Keywords: Deubiquitinase; Host-Pathogen interactions; Ubiquitin; a Ubiquitin E3 ligase.

Fig. 1.

(A). Legionella encodes specific E3 ubiquitin ligases LubX, which leads to the ubiquitination of eukaryotic Clk1 protein (Kubori et al., 2008), which is then targeted for proteasomal degradation. LubX also catalyzes the ubiquitination of bacterial protein SidH, leading to SidH degradation (Kubori et al., 2010). (B). Legionella encodes for an unusual E3 ligase SdeA, belonging to the SidE family (Qiu et al., 2016), which converts the ADP-ribose group on the ubiquitin to a phosphoribosyl group, which is attached SdeA, and finally, the ubiquitin moiety is transferred to Ser residues of substrate proteins such as Rab33b by using the phosphoribosyl group (Nordberg and Arner, 2001) without the requirement of E1 or E2 enzyme (Qiu et al., 2016). The function of SdeA s counteracted by a set of other Legionella effectors. First, SidJ might inactivate SdeA by SidJ-mediated glutamylation of SdeA (Bhogaraju et al., 2019). Second, DupA and DupB were recently identified as proteins that reverse the phosphoribosyl-linked serine ubiquitination by using their phosphodiesterase activity (Shin et al., 2020; Wan et al., 2019).