Mimicry by a viral
            <scp>RHIM</scp>

Mompeán, Miguel; Bozkurt, Günes; Wu, Hao

doi:10.15252/embr.201847433

Cited by 8 publications

(16 citation statements)

References 13 publications

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“…RHIMs consist of core tetrad ( ) residues promoting the stacking of β-sheet structures and formation of amyloid-like higher-order signaling complexes ( 14, 15, 32, 39, 40 ). Mutating these core tetrad residues inhibits the higher-order structure formation, cell death signaling, and inflammation ( 15, 20, 21, 23, 32, 33, 41, 42 ).…”

Section: Resultsmentioning

confidence: 99%

“…Type I IFNs promote inflammatory cell death as a protective host defense mechanism during viral infections ( 9, 12 ). Human receptor-interacting serine/threonine protein kinase 1 (RIPK1), RIPK3, Toll/IL-1 receptor domain-containing adapter protein-inducing IFN-β (TRIF), and Z-nucleic acid binding protein 1 (ZBP1) are inflammatory cell death signaling proteins ( 13, 14 ). These proteins have a conserved receptor-interacting protein (RIP)-homotypic interaction motif (RHIM), which confers protein-protein interactions of these cell death proteins.…”

Section: Introductionmentioning

confidence: 99%

“…These proteins have a conserved receptor-interacting protein (RIP)-homotypic interaction motif (RHIM), which confers protein-protein interactions of these cell death proteins. RHIM-mediated protein-protein interactions trigger the formation of higher-order signaling complexes, structurally resembling an amyloid fibrillar assembly, which promote cell death and inflammation ( 14–16 ). The RIPK3 in this complex mediates the activation of mixed lineage kinase domain-like (MLKL), leading to the execution of an inflammatory form of cell death necroptosis ( 15, 17, 18 ).…”

Section: Introductionmentioning

confidence: 99%

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Bat RNA viruses employ viral RHIMs orchestrating species-specific cell death programs linked to Z-RNA sensing and ZBP1-RIPK3 signaling

Mishra,

Jain,

Dey

et al. 2023

Preprint

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Interferons and regulated cell death pathways counteract virus spread and mount immune responses, but their deregulation often results in inflammatory pathologies. The RIP-homotypic interaction motif (RHIM) is a conserved protein domain critical for assembling higher-order amyloid-like signaling complexes inducing cell death. A few DNA viruses employ viral RHIMs mimicking host RHIMs to alleviate cell death-mediated antiviral defenses. Whether RNA viruses operate such viral RHIMs remains unknown. Host RHIM-protein signaling promotes lung damage and cytokine storm in respiratory RNA virus infections, arguing the presence of viral RHIMs in RNA viruses. Here, we report the identification of novel viral RHIMs in Nsp13 and Nsp14 of SARS-CoV-2 and other bat RNA viruses and provide a basis for bats as the hosts for the evolution of RHIMs in RNA viruses. Nsp13 expression promoted CoV-RHIM-1-dependent cell death after SARS-CoV-2 infection, and its RNA-binding channel conformation was critical for cell death function. Nsp13 interacted and promoted the formation of large insoluble complexes of ZBP1 and RIPK3. Unlike DNA virus RHIMs, SARS-CoV-2 Nsp13 did not restrict host RHIM-dependent cell death. Instead, it promoted ZBP1-RIPK3 signaling-mediated cell death dependent on intracellular RNA ligands. Intriguingly, SARS-CoV-2 genome fragments showed high Z-RNA forming propensity which bound to Z-RNA sensing Zα domains and promoted Nsp13-dependent cell death. Our findings reveal the functional viral RHIMs in RNA viruses and the role of SARS-CoV-2 Nsp13 in cell death associated with Z-RNAs and ZBP1-RIPK3 signaling, allowing the understanding of mechanisms of cellular damage and cytokine storm in respiratory virus infections and COVID-19.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Bat RNA viruses employ viral RHIMs orchestrating species-specific cell death programs linked to Z-RNA sensing and ZBP1-RIPK3 signaling

Mishra,

Jain,

Dey

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…We, therefore, synthesised TAT–RHIM peptides with a wide variety of different RHIM sequences. Valine (aa 58) in M45 located three positions upstream of the conserved RHIM core tetrad IQIG may be crucially involved in the interaction between RIPK3 and M45, and thus essential for the inhibitory properties of M45 in necroptosis [ 36 ]. If true, our original TAT– M45 RHIM peptide would have been too short, because the RHIM sequence we initially chose from M45 did not start until one amino acid after this valine.…”

Section: Resultsmentioning

confidence: 99%

TAT–RHIM: a more complex issue than expected

Kolbrink

Riebeling

Teiwes

et al. 2022

Biochemical Journal

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Murine cytomegalovirus protein M45 contains a RIP homotypic interaction motif (RHIM) that is sufficient to confer protection of infected cells against necroptotic cell death. Mechanistically, the N-terminal region of M45 drives rapid self-assembly into homo-oligomeric amyloid fibrils, and interacts with the endogenous RHIM domains of receptor-interacting protein kinases (RIPK) 1, RIPK3, Z-DNA binding protein 1, and TIR domain-containing adaptor-inducing interferon-β. Remarkably, all four mammalian proteins harbouring such a RHIM domain are key components of inflammatory signalling and regulated cell death processes. Immunogenic cell death by regulated necrosis causes extensive tissue damage in a wide range of diseases, including ischemia reperfusion injury, myocardial infarction, sepsis, stroke and organ transplantation. To harness the cell death suppression properties of M45 protein in a therapeutically usable manner, we developed a synthetic peptide encompassing only the RHIM domain of M45. To trigger delivery of RHIM into target cells, we fused the transactivator protein transduction domain of human immunodeficiency virus 1 to the N-terminus of the peptide. The fused peptide could efficiently penetrate eukaryotic cells, but unexpectedly it killed all tested cancer cell lines and primary cells irrespective of species without further stimulus through a necrosis-like cell death. Typical inhibitors of different forms of regulated cell death cannot impede this process, which appears to involve a direct disruption of biomembranes. Nevertheless, our finding has potential clinical relevance; reliable induction of a necrotic form of cell death distinct from all known forms of regulated cell death may offer a novel therapeutic approach to combat resistant tumour cells.

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“…The higher order structures of each viral fibril differs, likely reflecting the impact of residues outside the central core (Figure 1C and 4A). While M45 preferentially interacts with RIPK3 and ZBP1 over RIPK1, ORF20 primarily sequesters ZBP1 [49; 50]. These differences alter the functional outcomes.…”

Section: Discussionmentioning

confidence: 99%

Z-RNA and the flipside of the SARS Nsp13 helicase

Herbert

Shein²,

Poptsova

2022

Preprint

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We present evidence that the severe acute respiratory syndrome coronavirus (SARS) non-structural protein 13 (Nsp13) modulates the Z-RNA dependent regulated cell death pathway of necroptosis (1). We show that Z-prone sequences (called flipons (2)) exist in coronavirus and provide a signature that enables identification of the animal viruses which have become human pathogens. We also identify a potential RHIM in Nsp13. These two observations allow us to suggest a model in which Nsp13 may regulate Z-RNA-initiated RHIM-dependent cell death outcomes at two steps. The first step involves possible new ATP-independent Z-flipon helicase activity in Nsp13, which is distinct from the activity of the canonical A-RNA helicase. This activity unwinds/quenches nascent Z-RNAs, preventing their sensing by ZBP1. The second step involves RHIM-dependent inhibition of ZBP1, RIPK3 and/or RIPK1, preventing cell death downstream of Z-RNA sensing. Together the RHIM and Z-flipon helicase have the potential to alter the host response to the virus and the effectiveness of drugs targeting the NSP13 helicase.

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Mimicry by a viral RHIM

Cited by 8 publications

References 13 publications

Bat RNA viruses employ viral RHIMs orchestrating species-specific cell death programs linked to Z-RNA sensing and ZBP1-RIPK3 signaling

Bat RNA viruses employ viral RHIMs orchestrating species-specific cell death programs linked to Z-RNA sensing and ZBP1-RIPK3 signaling

TAT–RHIM: a more complex issue than expected

Z-RNA and the flipside of the SARS Nsp13 helicase

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