Disrupting the HDAC6-ubiquitin interaction impairs infection by influenza and Zika virus and cellular stress pathways
Copyright policy )Disrupting the HDAC6-ubiquitin interaction impairs infection by influenza and Zika virus and cellular stress pathways
The deacetylase HDAC6 has tandem catalytic domains and a zinc finger domain (ZnF) binding ubiquitin (Ub). While the catalytic domain has an antiviral effect, the ZnF facilitates influenza A virus (IAV) infection and cellular stress responses. By recruiting Ub via the ZnF, HDAC6 promotes the formation of aggresomes and stress granules (SGs), dynamic structures associated with pathologies such as neurodegeneration. IAV subverts the aggresome/HDAC6 pathway to facilitate capsid uncoating during early infection. To target this pathway, we generate designed ankyrin repeat proteins (DARPins) binding the ZnF; one of these prevents interaction with Ub in vitro and in cells. Crystallographic analysis shows that it blocks the ZnF pocket where Ub engages. Conditional expression of this DARPin reversibly impairs infection by IAV and Zika virus; moreover, SGs and aggresomes are downregulated. These results validate the HDAC6 ZnF as an attractive target for drug discovery.
Cell Reports, 39 (4)
ISSN:2666-3864
ISSN:2211-1247
- University of Bristol United Kingdom
- ETH Zurich Switzerland
- University of Bern Switzerland
- Nagoya University Japan
- University of Zurich Switzerland
stress granules, 610 Medicine & health, Histone Deacetylase 6, lysine deacetylases, HDAC6; influenza A virus; Zika virus; aggresome; stress granules; DARPin; ubiquitin; stress response; lysine deacetylases, Zika virus, 1300 General Biochemistry, Genetics and Molecular Biology, Report, aggresome, Influenza, Human, ubiquitin, 10019 Department of Biochemistry, Humans, influenza A virus, 630 Agriculture, Ubiquitin, Zika Virus Infection, Zika Virus, stress response, HDAC6, DARPin, Influenza A virus, 570 Life sciences; biology
stress granules, 610 Medicine & health, Histone Deacetylase 6, lysine deacetylases, HDAC6; influenza A virus; Zika virus; aggresome; stress granules; DARPin; ubiquitin; stress response; lysine deacetylases, Zika virus, 1300 General Biochemistry, Genetics and Molecular Biology, Report, aggresome, Influenza, Human, ubiquitin, 10019 Department of Biochemistry, Humans, influenza A virus, 630 Agriculture, Ubiquitin, Zika Virus Infection, Zika Virus, stress response, HDAC6, DARPin, Influenza A virus, 570 Life sciences; biology
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).32 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!