The Ubiquitination System within Bacterial Host–Pathogen Interactions

Abstract

Ubiquitination of proteins, like phosphorylation and acetylation, is an important regulatory aspect influencing numerous and various cell processes, such as immune response signaling and autophagy. The study of ubiquitination has become essential to learning about host–pathogen interactions, and a better understanding of the detailed mechanisms through which pathogens affect ubiquitination processes in host cell will contribute to vaccine development and effective treatment of diseases. Pathogenic bacteria (e.g., Salmonella enterica, Legionella pneumophila and Shigella flexneri) encode many effector proteins, such as deubiquitinating enzymes (DUBs), targeting the host ubiquitin machinery and thus disrupting pertinent ubiquitin-dependent anti-bacterial response. We focus here upon the host ubiquitination system as an integral unit, its interconnection with the regulation of inflammation and autophagy, and primarily while examining pathogens manipulating the host ubiquitination system. Many bacterial effector proteins have already been described as being translocated into the host cell, where they directly regulate host defense processes. Due to their importance in pathogenic bacteria progression within the host, they are regarded as virulence factors essential for bacterial evasion. However, in some cases (e.g., Francisella tularensis) the host ubiquitination system is influenced by bacterial infection, although the responsible bacterial effectors are still unknown.

The NEL Family of Bacterial E3 Ubiquitin Ligases

“…The RING E3 ligases promote the transfer of ubiquitin directly from E2 to the substrate, while the HECT and RBR ligases have a conserved cysteine residue where the ubiquitin binds before being transferred to the substrate, thus forming an intermediate E3-Ub. However, RBR ligases have interaction domains similar to those present in RING ligases [ 52 , 53 ].…”

The E3 ubiquitin ligase RNF115 regulates phagosome maturation and host response to bacterial infection

“…While ubiquitylation has been studied for many years in the endosomal system for its role in receptor sorting and multi-vesicular body (MVB) formation (Frankel & Audhya, 2018, Haglund & Dikic, 2012), and significant work has gone into characterising bacterial ubiquitin enzymes of intracellular pathogens such as Legionella (Vozandychova et al, 2021), little is known about the role of endogenous ubiquitylation on the phagosome. In 2005, it was shown that ubiquitin accumulates around the phagosome and that loss of E1 activity resulted in accumulation of Fc-receptors, suggesting a defect in the sorting of these receptors (Lee et al, 2005).…”

A novel innate pathogen sensing strategy involving ubiquitination of bacterial surface proteins

“…Interestingly, few pathogens are known to actively modify surface proteins, protecting them from ubiquitination and subsequent killing, thus emphasizing the significance of surface localization of the ubiquitin substrate (4). Additionally, multiple obligate intracellular pathogens have evolved strategies to de-ubiquitinate themselves or host regulatory components to evade ubiquitin mediated clearance (24). Taken together, these underscore ubiquitin-mediated alarm arousal as a fundamental intracellular pathogen sensing mechanism central to host defenses.…”