Large scale discovery of coronavirus-host factor protein interaction motifs reveals SARS-CoV-2 specific mechanisms and vulnerabilities

Kruse, Thomas; Benz, Caroline; Garvanska, Dimitriya H; Lindqvist, Richard; Mihalič, Filip; Coscia, Fabian; Inturi, Raviteja; Sayadi, Ahmed; Simonetti, Leandro; Nilsson, Emma; Ali, Muhammad; Kliche, Johanna; Morro, Ainhoa Moliner; Mund, Andreas; Andersson, Eva; McInerney, Gerald M.; Mann, Matthias; Jemth, Per; Davey, Norman E.; Överby, Anna K.; Nilsson, Jakob; Ivarsson, Ylva

doi:10.1038/s41467-021-26498-z

Cited by 56 publications

(56 citation statements)

References 75 publications

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“…Previous work identified an FGDF peptide motif in alphavirus nsP3 which binds with high affinity to G3BP [42,44]. More recent work characterizing viral-host interaction motifs has uncovered a conserved G3BP-binding motif, FxFG (where F is a hydrophobic residue) [45]. This G3BP interaction motif is present in both viral and host proteins, such as the cellular SG protein and known G3BP interactor USP10, and is remarkably similar to the alphavirus nsP3-G3BP interaction motif, FGDF, but likely binds with lower affinity [45].…”

Section: Trim25 Interacts With G3bp1 and 2 Through A Conserved Bindin...mentioning

confidence: 99%

“…This G3BP interaction motif is present in both viral and host proteins, such as the cellular SG protein and known G3BP interactor USP10, and is remarkably similar to the alphavirus nsP3-G3BP interaction motif, FGDF, but likely binds with lower affinity [45]. Moreover, TRIM25 was identified as a G3BP1 interaction partner [45]. Mutating the latter two amino acids in the TRIM25-specific motif (404-PTFG-407), to alanine (404-PTAA-407) was sufficient to abolish TRIM25-G3BP1 interaction [45].…”

Section: Trim25 Interacts With G3bp1 and 2 Through A Conserved Bindin...mentioning

confidence: 99%

“…Moreover, TRIM25 was identified as a G3BP1 interaction partner [45]. Mutating the latter two amino acids in the TRIM25-specific motif (404-PTFG-407), to alanine (404-PTAA-407) was sufficient to abolish TRIM25-G3BP1 interaction [45]. Meanwhile, TRIM25 and G3BP2 have previously been shown to interact in the context of prostate cancer [46].…”

Section: Trim25 Interacts With G3bp1 and 2 Through A Conserved Bindin...mentioning

confidence: 99%

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Elucidation of TRIM25 ubiquitination targets involved in diverse cellular and antiviral processes

et al. 2022

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The tripartite motif (TRIM) family of E3 ubiquitin ligases is well known for its roles in antiviral restriction and innate immunity regulation, in addition to many other cellular pathways. In particular, TRIM25-mediated ubiquitination affects both carcinogenesis and antiviral response. While individual substrates have been identified for TRIM25, it remains unclear how it regulates diverse processes. Here we characterized a mutation, R54P, critical for TRIM25 catalytic activity, which we successfully utilized to “trap” substrates. We demonstrated that TRIM25 targets proteins implicated in stress granule formation (G3BP1/2), nonsense-mediated mRNA decay (UPF1), nucleoside synthesis (NME1), and mRNA translation and stability (PABPC4). The R54P mutation abolishes TRIM25 inhibition of alphaviruses independently of the host interferon response, suggesting that this antiviral effect is a direct consequence of ubiquitination. Consistent with that, we observed diminished antiviral activity upon knockdown of several TRIM25-R54P specific interactors including NME1 and PABPC4. Our findings highlight that multiple substrates mediate the cellular and antiviral activities of TRIM25, illustrating the multi-faceted role of this ubiquitination network in modulating diverse biological processes.

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Section: Trim25 Interacts With G3bp1 and 2 Through A Conserved Bindin...mentioning

confidence: 99%

Section: Trim25 Interacts With G3bp1 and 2 Through A Conserved Bindin...mentioning

confidence: 99%

Section: Trim25 Interacts With G3bp1 and 2 Through A Conserved Bindin...mentioning

confidence: 99%

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Elucidation of TRIM25 ubiquitination targets involved in diverse cellular and antiviral processes

et al. 2022

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“…Upon interaction, attenuation of the host immune response occurs due to alteration of the process of stress granules inside the infected cells [74][75][76]. Kruse et al proposed that the nucleocapsid-induced inhibition of stress granules is due to the presence of the ΦxFG pattern motif in nucleocapsid, where Φ means any hydrophobic residue, X means any amino acid and the last two amino acids in the motif are phenylalanine and glycine [77]. The motif in SARS-CoV-2 does not follow the last part of the pattern in the ELM database [DES]F, which suggests that the exact pattern is not essential for the functionality of the motif.…”

Section: G3bp Protein Binding Motifmentioning

confidence: 99%

Dynamic, but Not Necessarily Disordered, Human-Virus Interactions Mediated through SLiMs in Viral Proteins

Elkhaligy

Balbin

Gonzalez

et al. 2021

Viruses

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Most viruses have small genomes that encode proteins needed to perform essential enzymatic functions. Across virus families, primary enzyme functions are under functional constraint; however, secondary functions mediated by exposed protein surfaces that promote interactions with the host proteins may be less constrained. Viruses often form transient interactions with host proteins through conformationally flexible interfaces. Exposed flexible amino acid residues are known to evolve rapidly suggesting that secondary functions may generate diverse interaction potentials between viruses within the same viral family. One mechanism of interaction is viral mimicry through short linear motifs (SLiMs) that act as functional signatures in host proteins. Viral SLiMs display specific patterns of adjacent amino acids that resemble their host SLiMs and may occur by chance numerous times in viral proteins due to mutational and selective processes. Through mimicry of SLiMs in the host cell proteome, viruses can interfere with the protein interaction network of the host and utilize the host-cell machinery to their benefit. The overlap between rapidly evolving protein regions and the location of functionally critical SLiMs suggest that these motifs and their functional potential may be rapidly rewired causing variation in pathogenicity, infectivity, and virulence of related viruses. The following review provides an overview of known viral SLiMs with select examples of their role in the life cycle of a virus, and a discussion of the structural properties of experimentally validated SLiMs highlighting that a large portion of known viral SLiMs are devoid of predicted intrinsic disorder based on the viral SLiMs from the ELM database.

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“…Proteins of viruses take over cellular host functions through short peptide interaction motifs (in unstructured regions) that bind to defined pockets on globular host domains. These motifs evolve by mutations, enabling viruses to interact with novel host factors ( Kruse et al, 2021 ). An understanding of these peptide-mediated protein-protein interactions could predict viral tropism and molecular processes within host cells ( Apostolopoulos et al, 2021 ).…”

Section: Short Peptides: the Most Versatile Biomoleculesmentioning

confidence: 99%

Smart therapies against global pandemics: A potential of short peptides

et al. 2022

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BackgroundAs we entered the third year of this pandemic, since the World Health Organisation (WHO) declared in March 2020 the novel coronavirus severe acute respiratory syndrome (SARS-CoV2) outbreak as a global pandemic COVID-19 (COronaVIrus Disease 19), we are still fighting with newer and newer viral mutations. The pandemic has passed the grim milestone of over 6.4 million COVID19 deaths, from more than 550 million reported cases thus far. In fact, more than 15 million people can die by the end of this year. It is highly likely that this pandemic will become endemic, while the full evolutionary potential of coronaviruses has yet to be revealed. The next pandemic is coming. A microbe with features of SARS-Middle East respiratory syndrome (MERS) and SARS-CoV-2 could lead to significantly more catastrophic loss of life. The co-evolution with other viruses should not be neglected. According to the WHO, we should expect diverse zoonotic, outbreakprone microbes, including highly pathogenic strains of influenza, Nipah, Ebola, Zika, or hemorrhagic fever viruses. 'It's an evolutionary certainty that there will be another virus with the potential to be more transmittable and deadly than this one', said Tedros Adhanom Ghebreyesus, director-general of the WHO. On the other hand, in both poor countries and regions of armed conflict, where vaccination is hampered, historic diseases are re-emerging, with migration and displacement influencing transmission risk and limiting control, and raising potential for additional outbreaks. Furthermore, there are other looming terrible threats to humanity as damaging as the bubonic plagues, such as bioterrorism or antibiotic resistant microorganisms. In most cases, both effective prevention and treatment options are limited.

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Large scale discovery of coronavirus-host factor protein interaction motifs reveals SARS-CoV-2 specific mechanisms and vulnerabilities

Cited by 56 publications

References 75 publications

Elucidation of TRIM25 ubiquitination targets involved in diverse cellular and antiviral processes

Elucidation of TRIM25 ubiquitination targets involved in diverse cellular and antiviral processes

Dynamic, but Not Necessarily Disordered, Human-Virus Interactions Mediated through SLiMs in Viral Proteins

Smart therapies against global pandemics: A potential of short peptides

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