Bacteria-host relationship: ubiquitin ligases as weapons of invasion

Abstract

Eukaryotic cells utilize the ubiquitin (Ub) system for maintaining a balanced functioning of cellular pathways. Although the Ub system is exclusive to eukaryotes, prokaryotic bacteria have developed an armory of Ub ligase enzymes that are capable of employing the Ub systems of various hosts, ranging from plant to animal cells. These enzymes have been acquired through the evolution and can be classified into three main classes, RING (really interesting new gene), HECT (homologous to the E6-AP carboxyl terminus) and NEL (novel E3 ligases). In this review we describe the roles played by different classes of bacterial Ub ligases in infection and pathogenicity. We also provide an overview of the different mechanisms by which bacteria mimic specific components of the host Ub system and outline the gaps in our current understanding of their functions. Additionally, we discuss approaches and experimental tools for validating this class of enzymes as potential novel antibacterial therapy targets.

Figure 1

Comparison of the NleL and SopA crystal structures. Ribbon representations of the NleL (PDB code: 3NB2) and SopA (PDB code: 2QYU) HECT-like bacterial Ub ligases. Catalytic cysteine residues of NleL (C753) and SopA (C753) are represented as red spheres. The amino (N) and carboxyl (C) lobes of the HECT domain are indicated, as well as the amino-terminal substrate recognition β-helix domain.

Figure 2

The carboxyl terminus of NleG effectors harbors RING/U-box domain. (A) Amino acid sequence alignment of NleG family member carboxy-terminal domains as analyzed by Clustal Omega^,. Conserved amino acids corresponding to the RING/U-box motif are denoted with asterisks. NleG family members with demonstrated Ub ligase activity in vitro are highlighted in bold italic. (B) Comparison of RING/U-box-like domains of AvrPtoB and NleG2-3. CTD structures of AvrPtoB (PDB code: 2FD4) and NleG2-3 (PDB code: 2KKY) were superimposed using Dalilite server. For clarity in comparison, peripheral elements of the CTDs are removed from both structures, showing only the core of the RING/U-box domains.

Figure 3

Structures of NELs from various pathogens. Ribbon representations of full-length NEL proteins (SspH2, SlrP, YopM, IpaH3), LRR (SspH1) and NEL (IpaH1.4) domains from various pathogens. Salmonella enteric SlrP and SspH1 structures are depicted in substrate-bound states. Catalytic cysteine residues of SspH1 (C580), SlrP (C546), IpaH3 (C363) and IpaH1.4 (C368) are represented as red spheres.