<i>Ehrlichia</i>
            SLiM Ligand Mimetic Activates Notch Signaling in Human Monocytes

Patterson, LaNisha L.; Velayutham, Thangam Sudha; Byerly, Caitlan D.; Bui, Duc-Cuong; Patel, Jignesh; Veljković, Veljko; Paessler, Slobodan; McBride, Jere W.

doi:10.1128/mbio.00076-22

Cited by 12 publications

(53 citation statements)

References 63 publications

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“…Moreover, during E . chaffeensis infection Wnt and Notch signaling pathways are activated through ligand mimicry via TRP120 Wnt and Notch SLiMs [ 3 , 5 ]. Since GLI-1 is a major transcriptional factor of the Hh signaling pathway and often cross-talks with Wnt and Notch signaling [ 37 , 38 ], we investigated the possibility of Hh pathway activation during E .…”

Section: Resultsmentioning

confidence: 99%

“…chaffeesis uses to reprogram the host cell using SLiM mimicry. We have identified an array of eukaryotic ligand SLiMs positioned in a single surface expressed effector protein that interface with the host cell and activate Notch, Wnt and now Hh signaling to counter innate defense mechanism and promote infection [ 3 , 5 ]. Collectively, these studies provide the molecular basis of eukaryotic pathway activation by an intracellular pathogen and provides a model that is valuable for understanding how pathogens interface with eukaryotic cells and rewire host cell pathways for infection.…”

Section: Discussionmentioning

confidence: 99%

“…Ehrlichia chaffeensis TRP120 is a moonlighting protein involved in modulating various cellular processes [ 6 ] and has evolved Wnt and Notch SLiMs to activate the conserved cellular signaling pathways [ 3 , 5 ]. In a recent report demonstrating Notch activation during E .…”

Section: Discussionmentioning

confidence: 99%

“…In a recent report demonstrating Notch activation during E . chaffeensis infection, we determined GLI-1 gene expression was activated by a Notch ligand SLiM in the TRP120 TR [ 5 , 36 ]. The intricate crosstalk between Wnt, Notch, and Hh signaling is well known; thus, we investigated the possibility of additional ligand SliMs and Hh pathway activation during E .…”

Section: Discussionmentioning

confidence: 99%

“…Recently, multiple TRP120 functions have been well defined including DNA binding [ 12 ], HECT E3 ubiquitin ligase activity [ 4 , 13 ], and ligand mimicry [ 3 ]. Notably, TRP120 engages Notch and Wnt receptors to activate conserved Notch and Wnt signaling through SLiM ligand mimicry [ 3 , 5 ]. SLiM ligand mimicry and post translational modification (PTM) SLiMs have been well characterized in bacteria and viruses [ 3 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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Ehrlichia chaffeensis (E. chaffeensis) has evolved eukaryotic ligand mimicry to repurpose 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 upregulation of Hh transcription factor GLI-1 and regulation 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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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

et al. 2022

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Orientia and Rickettsia: different flowers from the same garden

Gillespie¹,

Salje²

2023

Current Opinion in Microbiology

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EhrlichiaNotch signaling induction promotes XIAP stability and inhibits apoptosis

Patterson

Byerly

Solomon

et al. 2023

Preprint

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Ehrlichia chaffeensishas evolved multiple strategies to evade innate defenses of the mononuclear phagocyte. Recently, we reported theE. chaffeensisTRP120 effector functions as a Notch ligand mimetic and a ubiquitin ligase that degrades the nuclear tumor suppressor, F-box and WD repeat domain-containing 7 (FBW7), a negative regulator of Notch. The Notch receptor intracellular domain (NICD) is known to inhibit apoptosis primarily by interacting with X-linked inhibitor of apoptosis protein (XIAP) to prevent degradation. In this study, we determinedE. chaffeensisactivation of Notch signaling increases XIAP levels, thereby inhibiting intrinsic apoptosis. Increased NICD and XIAP levels were detected duringE. chaffeensisinfection and after TRP120 Notch ligand mimetic peptide treatment. Conversely, XIAP levels were reduced in the presence of Notch inhibitor DAPT. Cytoplasmic colocalization of NICD and XIAP was observed during infection and a direct interaction was confirmed by co-immunoprecipitation. Procaspase levels increased temporally during infection, consistent with increased XIAP levels; however, knockdown of XIAP during infection significantly increased apoptosis and Caspase-3, -7 and -9 levels. Further, treatment with SM-164, a second mitochondrial activator of caspases (Smac/DIABLO) antagonist, resulted in decreased procaspase levels and increased caspase activation, induced apoptosis, and significantly decreased infection. In addition, iRNA knockdown of XIAP also decreased infection and significantly increased apoptosis. Moreover, ectopic expression of TRP120 HECT Ub ligase catalytically defective mutant in HeLa cells decreased NICD and XIAP levels and increased caspase activation compared to WT. This investigation reveals a mechanism wherebyE. chaffeensisrepurposes Notch signaling to stabilize XIAP and inhibit apoptosis.

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Ehrlichia SLiM Ligand Mimetic Activates Notch Signaling in Human Monocytes

Cited by 12 publications

References 63 publications

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

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

Orientia and Rickettsia: different flowers from the same garden

EhrlichiaNotch signaling induction promotes XIAP stability and inhibits apoptosis

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