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.

Burkholderia pseudomallei suppresses Caenorhabditis elegans immunity by specific degradation of a GATA transcription factor

“…Pathogenic bacteria could suppress host immune response by inhibiting host translation (33,34), interfering with ubiquitination of signaling intermediates (35), or disrupting signaling complexes (36). For example, P. aeruginosa infection inhibits mRNA translation in the intestine via the endocytosed translation inhibitor Exotoxin A (33,34).…”

Heterogeneity of type III secretion system (T3SS)-1-independent entry mechanisms used by Salmonella Enteritidis to invade different cell types

“…The image is representative of two independent experiments. type IV and type VI secretion systems, may promote host cell membrane ruffling (Angot et al, 2007;Filloux et al, 2008).…”

Salmonella Secreted Factor L Deubiquitinase of Salmonella typhimurium Inhibits NF-κB, Suppresses IκBα Ubiquitination and Modulates Innate Immune Responses

“…Many animal and plant pathogenic bacteria use type III and/or IV secretion systems to inject effector proteins into host cells, where they subvert host signaling cascades, such as ubiquitination and/or NF-B activation (41,42). For example, the Yersinia type III effector protein YopJ, blocks signaling of the MAPK kinase and NF-B pathways by acetylating and/or deubiquitinating host MAPK kinases and NF-B-signaling kinases (TRAF6), thereby inactivating innate immune pathways (16 -19).…”