Ehrlichia chaffeensis TRP120 Is a Wnt Ligand Mimetic That Interacts with Wnt Receptors and Contains a Novel Repetitive Short Linear Motif That Activates Wnt Signaling

Rogan, Madison R.; Patterson, LaNisha L.; Byerly, Caitlan D.; Luo, Tian; Paessler, Slobodan; Veljković, Veljko; Quade, Bethany; McBride, Jere W.

doi:10.1128/msphere.00216-21

Cited by 17 publications

(100 citation statements)

References 88 publications

(143 reference statements)

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“…TRP120 contains a tandem repeat domain (TRD) centered between the N- and C- terminal domains. Various functional SLiMs have been reported within the N terminus, TRD, and C terminus that are relevant to E. chaffeensis infection, including posttranslational modification motifs, DNA-binding motifs, and ubiquitin ligase catalytic motifs (7). We previously reported that TRP120 stimulation results in transcriptional upregulation of GLI-1 in THP-1 cells (4).…”

Section: Resultsmentioning

confidence: 99%

“…We previously reported that TRP120 stimulation results in transcriptional upregulation of GLI-1 in THP-1 cells (4). Moreover, during E. chaffeensis infection Wnt and Notch signaling pathways are activated through ligand mimicry via TRP120 Wnt and Notch SLiMs (4, 7, 9, 10). Since GLI-1 is a major transcriptional factor of the Hh- signaling pathway and often cross-talks with Wnt and Notch signaling (35, 36), we investigated the possibility of Hh pathway activation during E. chaffeensis infection.…”

Section: Resultsmentioning

confidence: 99%

“…Subsequently, yeast-2-hybrid (Y2H) studies identified a multitude of molecular interactions between TRP120 and eukaryotic proteins involved in various cellular processes, including cell signaling, transcriptional regulation, PTMs and apoptosis (3). Recently, multiple TRP120 functions that have been well defined including DNA binding (11), HECT E3 ubiquitin ligase activity (6, 8, 12), and ligand mimicry (7). Notably, TRP120 engages Notch and Wnt receptors to activate conserved Notch and Wnt signaling through SLiM ligand mimicry (7, 9).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, multiple TRP120 functions that have been well defined including DNA binding (11), HECT E3 ubiquitin ligase activity (6, 8, 12), and ligand mimicry (7). Notably, TRP120 engages Notch and Wnt receptors to activate conserved Notch and Wnt signaling through SLiM ligand mimicry (7, 9). SLiM ligand mimicry and post translational modification (PTM) SLiMs have been well characterized in bacteria and viruses (7, 13, 14).…”

Section: Introductionmentioning

confidence: 99%

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Ehrlichia SLiM ligand mimetic activates Hedgehog signaling to engage a BCL-2 anti-apoptotic cellular program

Byerly

Mitra

Patterson

et al. 2022

Preprint

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Ehrlichia chaffeensis (E. chaffeensis) has evolved eukaryotic ligand mimicry to repurposes multiple cellular signaling pathways for immune evasion. In this investigation, we demonstrate that TRP120 has a novel repetitive short liner motif (SLiM) that activates the evolutionarily conserved Hedgehog (Hh) signaling pathway to inhibit apoptosis. In silico analysis revealed that TRP120 has sequence and functional similarity with Hh ligands and a candidate Hh ligand SLiM was identified. siRNA knockdown of Hh signaling and transcriptional components significantly reduced infection. Co-immunoprecipitation and surface plasmon resonance demonstrated that rTRP120-TR interacted directly with Hh receptor Patched-2 (PTCH2). E. chaffeensis infection resulted in early activation of Hh transcription factor GLI-1 and upregulation of Hh target genes. Moreover, soluble recombinant TRP120 (rTRP120) activated Hh and induced gene expression consistent with the eukaryotic Hh ligand. The TRP120 Hh SLiM (NPEVLIKD) induced nuclear translocation of GLI-1 in THP-1 cells and primary human monocytes and induced a rapid and expansive activation of Hh pathway target genes. Furthermore, Hh activation was blocked by an α-TRP120 Hh SLiM antibody. TRP120 Hh SLiM significantly increased levels of Hh target, anti-apoptotic protein B-cell lymphoma 2 (BCL-2), and siRNA knockdown of BCL-2 dramatically inhibited infection. Blocking Hh signaling with the inhibitor Vismodegib, induced a pro-apoptotic cellular program defined by decreased mitochondria membrane potential, significant reductions in BCL-2, activation of caspase 3 and 9, and increased apoptotic cells. This study reveals a novel E. chaffeensis SLiM ligand mimetic that activates Hh signaling to maintain E. chaffeensis infection by engaging a BCL-2 anti-apoptotic cellular program.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ehrlichia SLiM ligand mimetic activates Hedgehog signaling to engage a BCL-2 anti-apoptotic cellular program

Byerly

Mitra

Patterson

et al. 2022

Preprint

Self Cite

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“…TRP120 interacts with Wnt and Notch receptors to activate both pathways, regulating apoptosis and autophagy and promoting bacterial survival. Furthermore, TRP120 stability and interaction with Wnt FZD receptors stimulate bacterial internalization and the infection of host cells [95,96]. This effector also modulates the expression of several genes and, therefore, regulates multiple processes, including cytoskeleton organization and apoptosis [93].…”

Section: Ehrlichia Chaffeensismentioning

confidence: 99%

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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