Myxoma Virus-Encoded Host Range Protein M029: A Multifunctional Antagonist Targeting Multiple Host Antiviral and Innate Immune Pathways

Rahman, Masmudur M.; McFadden, Grant

doi:10.3390/vaccines8020244

Cited by 9 publications

(6 citation statements)

References 114 publications

(162 reference statements)

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“…Analysis of the two newly identified E3 homologs from CePV-TA shows that both present low identity to VACV E3, with CePV-TA-20 and CePV-TA-21 proteins only presenting sequence identity of 37% and 34%, respectively ( Figure 5B ). It is known that at the amino acid level, the C-terminal of E3-like proteins display a higher level of sequence similarity than the N-terminal domain ( 42 ). Accordingly, the dsRNA-BD domain from CePV-TA-20 and CePV-TA-21 proteins also display a higher level of sequence similarity compared to other E3 homologs ( Figure 5C ), suggesting that in CeTV this domain might also target conserved antiviral dsRNA-activated pathways.…”

Section: Resultsmentioning

confidence: 99%

Convergent Loss of the Necroptosis Pathway in Disparate Mammalian Lineages Shapes Viruses Countermeasures

et al. 2021

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Programmed cell death is a vital process in the life cycle of organisms. Necroptosis, an evolutionary form of programmed necrosis, contributes to the innate immune response by killing pathogen-infected cells. This virus-host interaction pathway is organized around two components: the receptor-interacting protein kinase 3 (RIPK3), which recruits and phosphorylates the mixed lineage kinase-like protein (MLKL), inducing cellular plasma membrane rupture and cell death. Critically, the presence of necroptotic inhibitors in viral genomes validates necroptosis as an important host defense mechanism. Here, we show, counterintuitively, that in different mammalian lineages, central components of necroptosis, such as RIPK3 and MLKL, are deleted or display inactivating mutations. Frameshifts or premature stop codons are observed in all the studied species of cetaceans and leporids. In carnivores’ genomes, the MLKL gene is deleted, while in a small number of species from afrotheria and rodentia premature stop codons are observed in RIPK3 and/or MLKL. Interestingly, we also found a strong correlation between the disruption of necroptosis in leporids and cetaceans and the absence of the N-terminal domain of E3-like homologs (responsible for necroptosis inhibition) in their naturally infecting poxviruses. Overall, our study provides the first comprehensive picture of the molecular evolution of necroptosis in mammals. The loss of necroptosis multiple times during mammalian evolution highlights the importance of gene/pathway loss for species adaptation and suggests that necroptosis is not required for normal mammalian development. Moreover, this study highlights a co-evolutionary relationship between poxviruses and their hosts, emphasizing the role of host adaptation in shaping virus evolution.

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Section: Resultsmentioning

confidence: 99%

Convergent Loss of the Necroptosis Pathway in Disparate Mammalian Lineages Shapes Viruses Countermeasures

et al. 2021

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“…Like other poxviruses, oncolytic MYXV can promiscuously bind, enter and initiate infection of most cancer cell types from different tissues and species. Still, successful productive replication that leads to progeny virus production and eventual killing of cancer cells largely depend on the viral manipulation of multiple intracellular signaling pathways (12, 31, 32). Every cancer cell has a unique spectrum of deficiencies in their cellular innate defence pathways that normally attempt to restrict virus infections, and so human cancer cells come in three general classes with respect to susceptibility to infection and killing by MYXV: fully permissive (ie produce viral progeny at levels comparable to rabbit cells), semi-permissive (ie produce at least an order of magnitude reduced levels of viral progeny) and nonpermissive (little or no viral progeny).…”

Section: Discussionmentioning

confidence: 99%

A novel anti-cancer therapy with nuclear export inhibitor Selinexor in combination with oncolytic myxoma virus

Rahman¹,

Oosterom²,

Enow³

et al. 2022

Preprint

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Oncolytic viruses exploited for cancer therapy are developed to selectively infect, replicate, and kill cancer cells to stop tumor growth. However, in some cancer cells, oncolytic viruses are often limited in completing their full replication cycle, making progeny virions, and/or spread in the tumor bed due to the heterogeneous cell types within the tumor bed. Here we report that nuclear export pathway regulates oncolytic myxoma virus (MYXV) infection and cytoplasmic viral replication in a subclass of human cancer cell types where virus replication is restricted. Inhibition of CRM1/XPO-1 nuclear export pathway with nuclear export inhibitors can overcome this restriction by trapping restriction factors in the nucleus and allow significantly enhanced virus replication and killing of human cancer cells. Furthermore, knockdown of CRM1/XPO-1 significantly enhanced MYXV replication in restrictive human cancer cells and reduced the formation of anti-viral granules associated with RNA helicase DHX9. Both in vitro and in vivo, we demonstrate that the approved CRM1 inhibitor drug Selinexor enhances the replication of MYXV and cell killing of diverse human cancer cells. In the xenograft tumor model in NSG mice, combination therapy with Selinexor plus MYXV significantly reduced tumor burden and enhanced the survival of animals. Additionally, we performed global scale proteomic analysis of nuclear and cytosolic proteins in human cancer cells to identify the host and viral proteins that are upregulated or downregulated by different treatments. These results for the first time indicate that Selinexor in combination with oncolytic MYXV can be used as potential new anti-cancer therapy.

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“…5B). It is known that at the amino acid level, the C-terminal of E3-like proteins display a higher level of sequence similarity than the N-terminal domain (Rahman and McFadden 2020). Accordingly, the dsRNA-BD domain from CePV-TA-20 and CePV-TA-21 proteins also display a higher level of sequence similarity compared to other E3 homologs (Fig.…”

Section: Diversity Among the Poxvirus Encoded E3-like Necroptosis Antagonistsmentioning

confidence: 98%

Convergent loss of the necroptosis pathway in disparate mammalian lineages shapes virus countermeasures

Águeda-Pinto

Alves

Neves³

et al. 2021

Preprint

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Programmed cell death is a vital process in the life cycle of an organism. Necroptosis, an evolutionary restricted form of programmed necrosis, contributes to the innate immune response by killing pathogen-infected cells. This virus-host interaction pathway is organized around two key components: the receptor-interacting protein kinase 3 (RIPK3), which recruits and phosphorylates the mixed lineage kinase-like protein (MLKL), thus inducing cellular plasma membrane rupture and cell death. Critically, the presence of necroptotic inhibitors in viral genomes validates necroptosis as an important host defense mechanism. Here, we show, counterintuitively, that in different mammalian lineages of mammalian, central components of the necroptotic pathway, such as RIPK3 and MLKL genes, are deleted or display inactivating mutations. Frameshifts or premature stop codons are observed in all the studied species of cetaceans and leporids. In carnivores' genomes, the MLKL gene is deleted, while in a small number of species from afrotheria and rodentia premature stop codons are observed in RIPK3 and/or MLKL. Interestingly, we also found a strong correlation between the disruption of necroptosis in leporids and cetaceans and the absence of the C-terminal domain of E3-like homologs (responsible for necroptosis inhibition) in their naturally infecting poxviruses. Overall, our study provides the first comprehensive picture of the molecular evolution of necroptosis in mammals. The loss of necroptosis multiple times during mammalian evolution highlights the importance of gene/pathway loss for species adaptation and suggests that necroptosis is not required for normal mammalian development. Moreover, this study highlights a co-evolutionary relationship between poxviruses and their hosts, emphasizing the role of host adaptation in shaping virus evolution.

show abstract

Myxoma Virus-Encoded Host Range Protein M029: A Multifunctional Antagonist Targeting Multiple Host Antiviral and Innate Immune Pathways

Cited by 9 publications

References 114 publications

Convergent Loss of the Necroptosis Pathway in Disparate Mammalian Lineages Shapes Viruses Countermeasures

Convergent Loss of the Necroptosis Pathway in Disparate Mammalian Lineages Shapes Viruses Countermeasures

A novel anti-cancer therapy with nuclear export inhibitor Selinexor in combination with oncolytic myxoma virus

Convergent loss of the necroptosis pathway in disparate mammalian lineages shapes virus countermeasures

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