GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:19557165

From GONUTS
Jump to: navigation, search
Citation

Chang, TH, Kubota, T, Matsuoka, M, Jones, S, Bradfute, SB, Bray, M and Ozato, K (2009) Ebola Zaire virus blocks type I interferon production by exploiting the host SUMO modification machinery. PLoS Pathog. 5:e1000493

Abstract

Ebola Zaire virus is highly pathogenic for humans, with case fatality rates approaching 90% in large outbreaks in Africa. The virus replicates in macrophages and dendritic cells (DCs), suppressing production of type I interferons (IFNs) while inducing the release of large quantities of proinflammatory cytokines. Although the viral VP35 protein has been shown to inhibit IFN responses, the mechanism by which it blocks IFN production has not been fully elucidated. We expressed VP35 from a mouse-adapted variant of Ebola Zaire virus in murine DCs by retroviral gene transfer, and tested for IFN transcription upon Newcastle Disease virus (NDV) infection and toll-like receptor signaling. We found that VP35 inhibited IFN transcription in DCs following these stimuli by disabling the activity of IRF7, a transcription factor required for IFN transcription. By yeast two-hybrid screens and coimmunoprecipitation assays, we found that VP35 interacted with IRF7, Ubc9 and PIAS1. The latter two are the host SUMO E2 enzyme and E3 ligase, respectively. VP35, while not itself a SUMO ligase, increased PIAS1-mediated SUMOylation of IRF7, and repressed Ifn transcription. In contrast, VP35 did not interfere with the activation of NF-kappaB, which is required for induction of many proinflammatory cytokines. Our findings indicate that Ebola Zaire virus exploits the cellular SUMOylation machinery for its advantage and help to explain how the virus overcomes host innate defenses, causing rapidly overwhelming infection to produce a syndrome resembling fulminant septic shock.

Links

PubMed PMC2696038 Online version:10.1371/journal.ppat.1000493

Keywords

Animals; Dendritic Cells/metabolism; Dendritic Cells/virology; Ebolavirus/genetics; Ebolavirus/immunology; Ebolavirus/physiology; Interferon Regulatory Factor-7/metabolism; Interferon-alpha/antagonists & inhibitors; Interferon-alpha/biosynthesis; Interferon-alpha/genetics; Interferon-beta/biosynthesis; Interferon-beta/genetics; Interferon-beta/metabolism; Mice; Mice, Inbred C57BL; NF-kappa B/antagonists & inhibitors; NF-kappa B/metabolism; Newcastle Disease/genetics; Newcastle Disease/metabolism; Newcastle disease virus/genetics; Promoter Regions, Genetic; Protein Inhibitors of Activated STAT/metabolism; Signal Transduction; Small Ubiquitin-Related Modifier Proteins/metabolism; Two-Hybrid System Techniques; Viral Regulatory and Accessory Proteins/genetics; Viral Regulatory and Accessory Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

EBOZM:VP35

involved_in

GO:0033235: positive regulation of protein sumoylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

EBOZM:VP35

GO:0033235: positive regulation of protein sumoylation

ECO:0000315:

P

Figure 7 shows that VP35 promotes SUMOylation of IRF7 positive regulation of the SUMO ligase, PIAS-1.

complete
CACAO 6882

MOUSE:TF65

GO:0005737: cytoplasm

ECO:0000314:

C

Figure 3B by immunostaining shows that in a control cell, p65 is located almost exclusively in the cytoplasm.

complete
CACAO 6881

MOUSE:TF65

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

See Help:References for how to manage references in GONUTS.