Use of viral motif mimicry improves the proteome-wide discovery of human linear motifs

Kleshchevnikov, Vitalii; Sandaltzopoulou, Elissavet; Benz, Caroline; Petsalaki, Evangelia

doi:10.1016/j.celrep.2022.110764

Cited by 10 publications

(9 citation statements)

References 105 publications

(152 reference statements)

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“…SLiMs drive evolution and rapidly evolve ex nihilo to add new functionality to proteins. Pathogens are known to convergently evolve SLiMs within disordered regions due to the limited number of mutations necessary for the generation of a new SLiM [ 68 ]. SLiMs contain high evolutionary plasticity due to their disordered nature, short length and limited number of specificity-determining residues [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

et al. 2022

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“…In recent years, viral mimicry has been suggested as one of the integral part of a viral infection, and researchers have been able to identify a number of novel viral SLiMs essential for their entry into hosts. Convergent evolution of the human SLiMs in viruses as well as the existence of simpler proteome compared to the humans can help us to identify novel SLiMs in humans [ 71 , 72 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular mimicry of host short linear motif-mediated interactions utilised by viruses for entry

2023

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Viruses are obligate intracellular parasites that depend on host cellular machinery for performing even basic biological functions. One of the many ways they achieve this is through molecular mimicry, wherein the virus mimics a host sequence or structure, thereby being able to hijack the host's physiological interactions for its pathogenesis. Such adaptations are specific recognitions that often confer tissue and species-specific tropisms to the virus, and enable the virus to utilise previously existing host signalling networks, which ultimately aid in further steps of viral infection, such as entry, immune evasion and spread. A common form of sequence mimicry utilises short linear motifs (SLiMs). SLiMs are short-peptide sequences that mediate transient interactions and are major elements in host protein interaction networks. This work is aimed at providing a comprehensive review of current literature of some well-characterised SLiMs that play a role in the attachment and entry of viruses into host cells, which mimic physiological receptor-ligand interactions already present in the host. Considering recent trends in emerging diseases, further research on such motifs involved in viral entry can help in the discovery of previously unknown cellular receptors utilised by viruses, as well as help in the designing of targeted therapeutics such as vaccines or inhibitors directed towards these interactions.

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“…As more data becomes readily available, analyses and discoveries can be improved and enhanced methods for identifying host-pathogen PPI facilitated through molecular mimicry can be developed. Recent work by Wadie et al applied structural and functional filters with information from viral SLiMs to enhance functional motif discovery in humans [ 61 ]. They used a low IUPRED2A disorder cutoff value of 0.2 to differentiate between functional and not functional SLiMs, but as we show here, caution must be taken when filtering viral SLiMs by IUPRED2A disorder even when using a very low cutoff value.…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of Structural Features in SLiMs from Eukaryotes, Bacteria, and Viruses with Importance for Host-Pathogen Interactions

Elkhaligy¹,

Balbin²,

Siltberg-Liberles³

2022

Pathogens

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Protein-protein interactions drive functions in eukaryotes that can be described by short linear motifs (SLiMs). Conservation of SLiMs help illuminate functional SLiMs in eukaryotic protein families. However, the simplicity of eukaryotic SLiMs makes them appear by chance due to mutational processes not only in eukaryotes but also in pathogenic bacteria and viruses. Further, functional eukaryotic SLiMs are often found in disordered regions. Although proteomes from pathogenic bacteria and viruses have less disorder than eukaryotic proteomes, their proteins can successfully mimic eukaryotic SLiMs and disrupt host cellular function. Identifying important SLiMs in pathogens is difficult but essential for understanding potential host-pathogen interactions. We performed a comparative analysis of structural features for experimentally verified SLiMs from the Eukaryotic Linear Motif (ELM) database across viruses, bacteria, and eukaryotes. Our results revealed that many viral SLiMs and specific motifs found across viruses and eukaryotes, such as some glycosylation motifs, have less disorder. Analyzing the disorder and coil properties of equivalent SLiMs from pathogens and eukaryotes revealed that some motifs are more structured in pathogens than their eukaryotic counterparts and vice versa. These results support a varying mechanism of interaction between pathogens and their eukaryotic hosts for some of the same motifs.

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Use of viral motif mimicry improves the proteome-wide discovery of human linear motifs

Cited by 10 publications

References 105 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

Molecular mimicry of host short linear motif-mediated interactions utilised by viruses for entry

Comparative Analysis of Structural Features in SLiMs from Eukaryotes, Bacteria, and Viruses with Importance for Host-Pathogen Interactions

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