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dc.contributor.author
Krawczyk, Krzysztof
dc.contributor.author
Scheller, Leo
dc.contributor.author
Kim, Hyojin
dc.contributor.author
Fussenegger, Martin
dc.date.accessioned
2020-02-10T07:37:39Z
dc.date.available
2020-02-08T03:12:26Z
dc.date.available
2020-02-10T07:37:39Z
dc.date.issued
2020
dc.identifier.issn
2041-1723
dc.identifier.other
10.1038/s41467-020-14397-8
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/397707
dc.identifier.doi
10.3929/ethz-b-000397707
dc.description.abstract
Rewiring cellular sensors to trigger non-natural responses is fundamental for therapeutic cell engineering. Current designs rely on engineered receptors that are limited to single inputs, and often suffer from high leakiness and low fold induction. Here, we present Generalized Engineered Activation Regulators (GEARs) that overcome these limitations by being pathway-specific rather than input-specific. GEARs consist of the MS2 bacteriophage coat protein fused to regulatory or transactivation domains, and work by rerouting activation of the NFAT, NFκB, MAPK or SMAD pathways to dCas9-directed gene expression from genomic loci. This system enables membrane depolarization-induced activation of insulin expression in β-mimetic cells and IL-12 expression in activated Jurkat cells, as well as IL-12 production in response to the immunomodulatory cytokines TGFβ and TNFα in HEK293T cells. Engineered cells with the ability to reinterpret the extracellular milieu have potential for applications in immunotherapy and in the treatment of metabolic diseases.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Nature
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.title
Rewiring of endogenous signaling pathways to genomic targets for therapeutic cell reprogramming
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
dc.date.published
2020-01-30
ethz.journal.title
Nature Communications
ethz.journal.volume
11
en_US
ethz.journal.issue
1
en_US
ethz.journal.abbreviated
Nat Commun
ethz.pages.start
608
en_US
ethz.size
9 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
London
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02060 - Dep. Biosysteme / Dep. of Biosystems Science and Eng.::03694 - Fussenegger, Martin / Fussenegger, Martin
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02060 - Dep. Biosysteme / Dep. of Biosystems Science and Eng.::03694 - Fussenegger, Martin / Fussenegger, Martin
ethz.relation.isPartOf
10.3929/ethz-b-000447722
ethz.date.deposited
2020-02-08T03:12:40Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2020-02-10T07:37:50Z
ethz.rosetta.lastUpdated
2024-02-02T10:20:47Z
ethz.rosetta.versionExported
true
ethz.COinS
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