Exploitation of eukaryotic ubiquitin signaling pathways by effectors translocated by bacterial type III and type IV secretion systems

Abstract

The specific and covalent addition of ubiquitin to proteins, known as ubiquitination, is a eukaryotic-specific modification central to many cellular processes, such as cell cycle progression, transcriptional regulation, and hormone signaling. Polyubiquitination is a signal for the 26S proteasome to destroy earmarked proteins, but depending on the polyubiquitin chain topology, it can also result in new protein properties. Both ubiquitin-orchestrated protein degradation and modification have also been shown to be essential for the host's immune response to pathogens. Many animal and plant pathogenic bacteria utilize type III and/or type IV secretion systems to inject effector proteins into host cells, where they subvert host signaling cascades as part of their infection strategy. Recent progress in the determination of effector function has taught us that playing with the host's ubiquitination system seems a general tactic among bacteria. Here, we discuss how bacteria exploit this system to control the timing of their effectors' action by programming them for degradation, to block specific intermediates in mammalian or plant innate immunity, or to target host proteins for degradation by mimicking specific ubiquitin/proteasome system components. In addition to analyzing the effectors that have been described in the literature, we screened publicly available bacterial genomes for mimicry of ubiquitin proteasome system subunits and detected several new putative effectors. Our understanding of the intimate interplay between pathogens and their host's ubiquitin proteasome system is just beginning. This exciting research field will aid in better understanding this interplay, and may also provide new insights into eukaryotic ubiquitination processes.

Figure 1. The Eukaryotic UPS

Schematic representation of signaling in the UPS, which requires a series of enzymatic steps involving E1, E2, and E3 enzyme complexes that will eventually lead to the addition of Ub moieties to target proteins. The specific recognition of substrates (yellow) by an E3 Ub ligase generally depends on the prior phosphorylation of the substrate (not indicated in the figure). Different types of ubiquitination can lead to different modifications, from proteasome degradation (for the K48-linked poly-Ub chain) to modification in protein properties (K63, oligo Ub [5]). Note that the scheme presented here applies to RING-type E3 ligases; in HECT-type E3s the Ub moiety is transferred from the E2 onto the conserved cystein of the HECT protein, which then transfers this Ub onto the target protein (see text for details).

Figure 2. T3/4SS Effectors Interfering with the Host UPS

After T3/4SS-mediated translocation into the host cell, several effectors (black-boxes) of diverse bacteria can target different steps of the UPS: some effectors have been shown to inhibit specific steps (e.g., inhibit an E3 Ub ligase, such as OspG, or deubiquitinate subtrates like YopJ and YopP), mimic different UPS E3 Ub ligase subunits (here represented as one black subunit for simplicity as VirF, AvrPtoB, GALA, and SopA), or act as possible adaptor to target substrates to the E3 ligase (HopM1). Eventually, effectors can be a substrate for the UPS, like ExoU, SopB, SopE, and YopE (black ellipses). Table 1 describes in more detail the effectors presented in this figure. “Salmonella factor(s)?” refers to unknown factors from non-pathogenic and attenuated Salmonella strains (see text).

Figure 3. T3SS Effectors Interfering with Ub Signaling in the Mammalian Innate Immune Response

Ubiquitination plays an important regulatory role in different steps of the innate immune signaling cascades. This simplified representation shows the different levels at which T3SS effectors (black-boxes) thus far have been shown to interfere with the pro-inflammatory host immune response; this interference can be at the signaling node represented by the TAK1 complex (affecting both NF-κB and the MAPK signaling pathways), or downstream of TAK1, only affecting the NF-κB pathway. Numbers in brackets indicate the specific references. Details of the immune signaling are given in the text.