<i>Ehrlichia</i> TRP effectors: moonlighting, mimicry and infection

Byerly, Caitlan D.; Patterson, La Nisha L.; McBride, Jere W.

doi:10.1093/femspd/ftab026

Cited by 27 publications

(45 citation statements)

References 82 publications

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Section: Ehrlichia Chaffeensismentioning

confidence: 99%

“…Ehrlichia chaffeensis tandem repeat protein (TRP) effectors secreted by the type 1 secretion system (T1SS) and their diverse and continually expanding roles in infection have been extensively reviewed recently [93]. Among TRPs, TRP120 effector is considered a model moonlighting protein [93,94]. The most well-documented functions of this effector comprise ligand mimic, nucleomodulin, and E3 ubiquitin ligase activity, although additional roles have been proposed [93].…”

Section: Ehrlichia Chaffeensismentioning

confidence: 99%

“…Among TRPs, TRP120 effector is considered a model moonlighting protein [93,94]. The most well-documented functions of this effector comprise ligand mimic, nucleomodulin, and E3 ubiquitin ligase activity, although additional roles have been proposed [93]. TRP120 interacts with Wnt and Notch receptors to activate both pathways, regulating apoptosis and autophagy and promoting bacterial survival.…”

Section: Ehrlichia Chaffeensismentioning

confidence: 99%

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Moonlighting in Rickettsiales: Expanding Virulence Landscape

2022

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The order Rickettsiales includes species that cause a range of human diseases such as human granulocytic anaplasmosis (Anaplasma phagocytophilum), human monocytic ehrlichiosis (Ehrlichia chaffeensis), scrub typhus (Orientia tsutsugamushi), epidemic typhus (Rickettsia prowazekii), murine typhus (R. typhi), Mediterranean spotted fever (R. conorii), or Rocky Mountain spotted fever (R. rickettsii). These diseases are gaining a new momentum given their resurgence patterns and geographical expansion due to the overall rise in temperature and other human-induced pressure, thereby remaining a major public health concern. As obligate intracellular bacteria, Rickettsiales are characterized by their small genome sizes due to reductive evolution. Many pathogens employ moonlighting/multitasking proteins as virulence factors to interfere with multiple cellular processes, in different compartments, at different times during infection, augmenting their virulence. The utilization of this multitasking phenomenon by Rickettsiales as a strategy to maximize the use of their reduced protein repertoire is an emerging theme. Here, we provide an overview of the role of various moonlighting proteins in the pathogenicity of these species. Despite the challenges that lie ahead to determine the multiple potential faces of every single protein in Rickettsiales, the available examples anticipate this multifunctionality as an essential and intrinsic feature of these obligates and should be integrated into available moonlighting repositories.

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Section: Ehrlichia Chaffeensismentioning

confidence: 99%

Section: Ehrlichia Chaffeensismentioning

confidence: 99%

Section: Ehrlichia Chaffeensismentioning

confidence: 99%

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Moonlighting in Rickettsiales: Expanding Virulence Landscape

2022

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“…This review primarily focuses on recent findings pertaining to invasin, Type IV secretion system (T4SS) effectors, and host-cell membrane lipids that are acquired by E. chaffeensis. Readers are referred to several informative reviews for discussion of other aspects of E. chaffeensis (Paddock and Childs, 2003;Rikihisa, 2010;McBride and Walker, 2011;Rikihisa, 2011;Rikihisa, 2015;McClure et al, 2017;Byerly et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

The “Biological Weapons” of Ehrlichia chaffeensis: Novel Molecules and Mechanisms to Subjugate Host Cells

Rikihisa

2022

Front. Cell. Infect. Microbiol.

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Ehrlichia chaffeensis is an obligatory intracellular bacterium that causes human monocytic ehrlichiosis, an emerging, potentially fatal tick-borne infectious disease. The bacterium enters human cells via the binding of its unique outer-membrane invasin EtpE to the cognate receptor DNase X on the host-cell plasma membrane; this triggers actin polymerization and filopodia formation at the site of E. chaffeensis binding, and blocks activation of phagocyte NADPH oxidase that catalyzes the generation of microbicidal reactive oxygen species. Subsequently, the bacterium replicates by hijacking/dysregulating host-cell functions using Type IV secretion effectors. For example, the Ehrlichia translocated factor (Etf)-1 enters mitochondria and inhibits mitochondria-mediated apoptosis of host cells. Etf-1 also induces autophagy mediated by the small GTPase RAB5, the result being the liberation of catabolites for proliferation inside host cells. Moreover, Etf-2 competes with the RAB5 GTPase-activating protein, for binding to RAB5-GTP on the surface of E. chaffeensis inclusions, which blocks GTP hydrolysis and consequently prevents the fusion of inclusions with host-cell lysosomes. Etf-3 binds ferritin light chain to induce ferritinophagy to obtain intracellular iron. To enable E. chaffeensis to rapidly adapt to the host environment and proliferate, the bacterium must acquire host membrane cholesterol and glycerophospholipids for the purpose of producing large amounts of its own membrane. Future studies on the arsenal of unique Ehrlichia molecules and their interplay with host-cell components will undoubtedly advance our understanding of the molecular mechanisms of obligatory intracellular infection and may identify hitherto unrecognized signaling pathways of human hosts. Such data could be exploited for development of treatment and control measures for ehrlichiosis as well as other ailments that potentially could involve the same host-cell signaling pathways that are appropriated by E. chaffeensis.

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“…TRPs are secreted intracellularly during infection by the type-1 secretion system, where they interact in a spatial and context-dependent manner with a diverse array of host cell proteins involved in essential cellular processes [ 4 , 5 , 6 , 7 , 8 , 9 ]. Most recently, E. chaffeensis TRP120 effector was shown to act as a ligand mimic that activates Wnt and Notch signaling pathways, as well as possessing other moonlighting functions during infection [ 10 , 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Alpha Enolase 1 Ubiquitination and Degradation Mediated by Ehrlichia chaffeensis TRP120 Disrupts Glycolytic Flux and Promotes Infection

Zhu

McBride

2021

Pathogens

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Ehrlichia chaffeensis modulates numerous host cell processes, including gene transcription to promote infection of the mononuclear phagocyte. Modulation of these host cell processes is directed through E. chaffeensis effectors, including TRP120. We previously reported that TRP120 moonlights as a HECT E3 Ub ligase that ubiquitinates host cell transcription and fate regulators (PCGF5 and FBW7) to promote infection. In this study, we identified a novel TRP120 substrate and examined the relationship between TRP120 and α-enolase (ENO1), a metalloenzyme that catalyzes glycolytic pathway substrate dehydration. Immunofluorescence microscopy and coimmunoprecipitation demonstrated interaction between ENO1 and TRP120, and ubiquitination of ENO-1 by TRP120 was detected in vivo and in vitro. Further, ENO-1 degradation was observed during infection and was inhibited by the proteasomal inhibitor bortezomib. A direct role of TRP120 Ub ligase activity in ENO-1 degradation was demonstrated and confirmed by ectopic expression of TRP120 HECT Ub ligase catalytic site mutant. siRNA knockdown of ENO-1 coincided with increased E. chaffeensis infection and ENO-1 knockdown disrupted glycolytic flux by decreasing the levels of pyruvate and lactate that may contribute to changes in host cell metabolism that promote infection. In addition, we elucidated a functional role of TRP120 auto-ubiquitination as an activating event that facilitates the recruitment of the UbcH5 E2 ubiquitin-conjugating enzyme. This investigation further expands the repertoire of TRP120 substrates and extends the potential role of TRP120 Ub ligase in infection to include metabolic reprogramming.

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Ehrlichia TRP effectors: moonlighting, mimicry and infection

Cited by 27 publications

References 82 publications

Moonlighting in Rickettsiales: Expanding Virulence Landscape

Moonlighting in Rickettsiales: Expanding Virulence Landscape

The “Biological Weapons” of Ehrlichia chaffeensis: Novel Molecules and Mechanisms to Subjugate Host Cells

Alpha Enolase 1 Ubiquitination and Degradation Mediated by Ehrlichia chaffeensis TRP120 Disrupts Glycolytic Flux and Promotes Infection

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