The VSV matrix protein inhibits NF-κB and the interferon response independently in mouse L929 cells

Marquis, Kaitlin A.; Becker, Rachel L.; Weiss, Amanda N.; Morris, Matthew C.; Ferran, Maureen C.

doi:10.1016/j.virol.2020.06.013

Cited by 10 publications

(9 citation statements)

References 35 publications

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“…The D52G mutation in the M protein of the 22–20 strain appears to have perturbed its ability to block NFκB activation in L929 cells. Thus, 22–20 VSV, unlike the wt and 22–25 strains, cannot rely on NFκB inhibition for immune evasion, and instead inhibits host IFN production via an independent suppressor function [ 34 ]. These predictions can be partially validated by comparison with existing descriptions of VSV targets.…”

Section: Discussionmentioning

confidence: 99%

“…Its sister plaque isolate, 22–25, did not contain a mutation in this highly conserved region of M and retained the ability to block NFκB activation [ 33 ]. IFN mRNA and protein were produced in L929 cells infected with viruses encoding the M(M51R) mutation, however little to no IFN mRNA or protein was produced in wt, 22–25, or 22-20-infected L929 cells [ 34 ]. It is thus likely that VSV M protein has multiple independent means of interfering with immune activation by acting on distinct cellular targets.…”

Section: Introductionmentioning

confidence: 99%

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Computational prediction of intracellular targets of wild-type or mutant vesicular stomatitis matrix protein

et al. 2022

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The matrix (M) protein of vesicular stomatitis virus (VSV) has a complex role in infection and immune evasion, particularly with respect to suppression of Type I interferon (IFN). Viral strains bearing the wild-type (wt) M protein are able to suppress Type I IFN responses. We recently reported that the 22–25 strain of VSV encodes a wt M protein, however its sister plaque isolate, strain 22–20, carries a M[MD52G] mutation that perturbs the ability of the M protein to block NFκB, but not M-mediated inhibition of host transcription. Therefore, although NFκB is activated in 22–20 infected murine L929 cells infected, no IFN mRNA or protein is produced. To investigate the impact of the M[D52G] mutation on immune evasion by VSV, we used transcriptomic data from L929 cells infected with wt, 22–25, or 22–20 to define parameters in a family of executable logical models with the aim of discovering direct targets of viruses encoding a wt or mutant M protein. After several generations of pruning or fixing hypothetical regulatory interactions, we identified specific predicted targets of each strain. We predict that wt and 22–25 VSV both have direct inhibitory actions on key elements of the NFκB signaling pathway, while 22–20 fails to inhibit this pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Computational prediction of intracellular targets of wild-type or mutant vesicular stomatitis matrix protein

et al. 2022

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“…These viruses can also invoke anti-tumoral adaptive responses in vivo. For example, VSV strains encoding a deletion or arginine substitution of methionine 51 in the VSV matrix (M) protein (VSVM51/M51R) are being intensively pursued as a potential oncolytic agent [63][64][65][66][67][68]. These strains display a relatively safe profile because their mutant M proteins are unable to block cellular gene expression and thus are highly susceptible to innate immune responses (e.g.…”

Section: Ipah4 Activity or Shoc2/psmc1 Depletion Breaks The Restricti...mentioning

confidence: 99%

“…These strains display a relatively safe profile because their mutant M proteins are unable to block cellular gene expression and thus are highly susceptible to innate immune responses (e.g. IFN signaling) that are present in normal cells, but typically defective in transformed cells [63][64][65][66][67][68]. However, a wide array of human cancer cell lines and tumor types have been shown to be refractory to VSVM51/M51R replication, presumably due restriction pathways that are still active in transformed cells [69][70][71][72][73].…”

Section: Ipah4 Activity or Shoc2/psmc1 Depletion Breaks The Restricti...mentioning

confidence: 99%

Exploiting Bacterial Effector Proteins to Uncover Evolutionarily Conserved Antiviral Host Machinery

Embry,

Baggett,

Heisler

et al. 2024

Preprint

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Arboviruses are a diverse group of insect-transmitted pathogens that pose global public health challenges. Identifying evolutionarily conserved host factors that combat arbovirus replication in disparate eukaryotic hosts is important as they may tip the balance between productive and abortive viral replication, and thus determine virus host range. Here, we exploit naturally abortive arbovirus infections that we identified in lepidopteran cells and use bacterial effector proteins to uncover host factors restricting arbovirus replication. Bacterial effectors are proteins secreted by pathogenic bacteria into eukaryotic hosts cells that can inhibit antimicrobial defenses. Since bacteria and viruses can encounter common host defenses, we hypothesized that some bacterial effectors may inhibit host factors that restrict arbovirus replication in lepidopteran cells. Thus, we used bacterial effectors as molecular tools to identify host factors that restrict four distinct arboviruses in lepidopteran cells. By screening 210 effectors encoded by seven different bacterial pathogens, we identify six effectors that individually rescue the replication of all four arboviruses. We show that these effectors encode diverse enzymatic activities that are required to break arbovirus restriction. We further characterizeShigella flexneri-encoded IpaH4 as an E3 ubiquitin ligase that directly ubiquitinates two evolutionarily conserved proteins, SHOC2 and PSMC1, promoting their degradation in insect and human cells. We show that depletion of either SHOC2 or PSMC1 in insect or human cells promotes arbovirus replication, indicating that these are ancient virus restriction factors conserved across invertebrate and vertebrate hosts. Collectively, our study reveals a novel pathogen-guided approach to identify conserved antimicrobial machinery, new effector functions, and conserved roles for SHOC2 and PSMC1 in virus restriction.Author SummaryMicrobial pathogens such as viruses and bacteria encounter diverse host cell responses during infection. While viruses possess antagonists to counter these responses in natural host species, their replication can be restricted in unnatural host cells where their antagonists are ineffective. Bacteria also employ a diverse repertoire of immune evasion proteins known as “effectors” that can inhibit antimicrobial responses found in invertebrate and vertebrate hosts. In this study, we hypothesized that some bacterial effectors may target host immunity proteins that restrict both bacteria and viruses. To test this hypothesis, we screened a bacterial effector library comprising 210 effectors from seven distinct bacterial pathogens for their ability to rescue the replication of four viruses in insect cells that are normally non-permissive to these viruses. Though numerous effectors were identified to rescue the replication of each virus, the uncharacterized IpaH4 protein encoded by the human pathogenShigella flexneriwas able to rescue all four viruses screened. We discovered that IpaH4 enhances arbovirus replication in both restrictive insect and permissive human cells by directly targeting two novel, evolutionarily conserved antiviral host proteins, SHOC2 and PSMC1, for degradation. Our study establishes bacterial effectors as valuable tools for identifying critical antimicrobial machinery employed by eukaryotic hosts.

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“…host IFN production via an independent suppressor function [34]. These predictions can be partially validated by comparison with existing descriptions of VSV targets.…”

Section: Plos Onementioning

confidence: 78%

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The VSV matrix protein inhibits NF-κB and the interferon response independently in mouse L929 cells

Cited by 10 publications

References 35 publications

Computational prediction of intracellular targets of wild-type or mutant vesicular stomatitis matrix protein

Computational prediction of intracellular targets of wild-type or mutant vesicular stomatitis matrix protein

Exploiting Bacterial Effector Proteins to Uncover Evolutionarily Conserved Antiviral Host Machinery

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