Abstract
Ubiquitin, a highly conserved polypeptide of 76 amino acids, participates in a vast range of eukaryotic cell processes through its role as a reversible post-translational modifier (see review [1], Figure 1A). Such extensive utilization of a single protein within a host cell lends itself to be an ideal target for microbial manipulation. Host-pathogen co-evolution has endowed present-day pathogens with an ever-expanding repertoire of proteins that function to modulate this system. The majority of these proteins are effectors of type III secretion (T3S) or type IV secretion (T4S) pathways, which are major virulence determinants of many Gram-negative pathogens [2], [3]. This review is focused on five distinct mechanisms in which secreted bacterial effector proteins exploit the host ubiquitylation system (Figure 2). Figure 1 The three classes of host enzymes (E1, purple; E2, red; E3, yellow) involved in ubiquitin modification of target host proteins. Figure 2 Five distinct mechanisms in which bacterial proteins manipulate the host ubiquitin system.
Highlights
Effector ModificationBacterial pathogens have evolved effectors that allow the host ubiquitin system to fine-tune their function, localization, or temporal regulation
One method to disrupt host cell physiology involves the injection of bacterial effectors that mimic proteins in the final step of ubiquitylation involving the E3 ligases [4]
RING ligases act as bridging partners between E2ubiquitin conjugates and target proteins, while HECT ligases directly participate in the chemistry of ubiquitylation (Figure 1B) [5,6]
Summary
Bacterial pathogens have evolved effectors that allow the host ubiquitin system to fine-tune their function, localization, or temporal regulation. Diversification of effector function and localization through ubiquitylation has been demonstrated for the Salmonella phosphoinositide phosphatase, SopB. In this case, an enzyme with a single catalytic function can act to modulate multiple cellular processes depending on its ubiquitylation state. Deamidation of glutamine 100 to glutamate on the E2 prevents polyubiquitylation of the E3 and activation of downstream innate immune response [21] Host enzymes such as DUBS can play scaffolding roles for bacterial effectors to enhance virulence. Cif stabilizes an intracellular complex of a DUB (USP10) and G3BP1, preventing deubiquitylation of CFTR, which is required for recycling the receptor to the plasma membrane [22]. The finesse of each of these effectors greatly enhances their specificity and prevents unintended collateral damage that might stimulate further inflammatory responses
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