The NEL Family of Bacterial E3 Ubiquitin Ligases

Abstract

Some pathogenic or symbiotic Gram-negative bacteria can manipulate the ubiquitination system of the eukaryotic host cell using a variety of strategies. Members of the genera Salmonella, Shigella, Sinorhizobium, and Ralstonia, among others, express E3 ubiquitin ligases that belong to the NEL family. These bacteria use type III secretion systems to translocate these proteins into host cells, where they will find their targets. In this review, we first introduce type III secretion systems and the ubiquitination process and consider the various ways bacteria use to alter the ubiquitin ligation machinery. We then focus on the members of the NEL family, their expression, translocation, and subcellular localization in the host cell, and we review what is known about the structure of these proteins, their function in virulence or symbiosis, and their specific targets.

Keywords: E3 ubiquitin ligases; Ralstonia; Salmonella; Shigella; Sinorhizobium; effectors; type III secretion.

Figure 4

Crystal structures of NEL E3 ligases. (A) Examples of the two autoinhibition modes: SspH2, mode 1 (PDB ID: 3G06) [108]; IpaHc, mode2 (PDB ID: 3CVR) [56]. Colors are set according to secondary structure. (B) E3 ligases in complex with their substrates: SlrP (blue) in complex with Trx1 (red and yellow) (PDB ID: 4PUF) [179]; the LRR domain of SspH1 (dark blue) in complex with the HR1b domain of PKN1 (light blue) (4NKG) [186]; the LRR domain of IpaH9.8 (blue) in complex with GBP1 (red) (PDB ID: 6LOJ) [185]; and the LRR domain of IpaH1.4 (blue) in complex with the RING1 domain of HOIP (red) (PDB ID: 7V8G) [187]. Drawings created with NGL [191].

Figure 1

Clusters of genes that encode T3SSs. SPI1 and SPI2 from S. enterica serovar Typhimurium, the entry region from S. flexneri, the tts cluster from S. fredii, and the hrp cluster from R. solanacearum.

Figure 2

Diagram of domain structure of effectors of the NEL family of E3 ubiquitin ligases: IpaH proteins from S. flexneri; NopM from S. fredii; RipAR, RipAW, RipV1, and RipV2 from R. solanacearum; SlrP, SspH1, SspH2, and SspH3 from S. enterica. Boundaries for each domain are numbered according to the InterProScan predictions [99].

Figure 3

Phylogenetic analysis of NEL effectors. Alignment and phylogenetic reconstructions were performed using the function “build” of ETE3 v3.1.1 [125] as implemented on the GenomeNet (https://www.genome.jp/tools/ete/, accessed on 14 May 2022). Alignment was performed with Clustal Omega v1.2.1 with the default options [126]. The tree was constructed using FastTree v2.1.8 with default parameters [127].