Engineering synthetic phosphorylation signaling networks in human cells.
Journal
bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187
Informations de publication
Date de publication:
14 Nov 2023
14 Nov 2023
Historique:
pubmed:
25
9
2023
medline:
25
9
2023
entrez:
25
9
2023
Statut:
epublish
Résumé
Protein phosphorylation signaling networks play a central role in how cells sense and respond to their environment. Here, we describe the engineering of artificial phosphorylation networks in which "push-pull" motifs-reversible enzymatic phosphorylation cycles consisting of opposing kinase and phosphatase activities-are assembled from modular protein domain parts and then wired together to create synthetic phosphorylation circuits in human cells. We demonstrate that the composability of our design scheme enables model-guided tuning of circuit function and the ability to make diverse network connections; synthetic phosphorylation circuits can be coupled to upstream cell surface receptors to enable fast-timescale sensing of extracellular ligands, while downstream connections can regulate gene expression. We leverage these capabilities to engineer cell-based cytokine controllers that dynamically sense and suppress activated T cells. Our work introduces a generalizable approach for designing and building phosphorylation signaling circuits that enable user-defined sense-and-respond function for diverse biosensing and therapeutic applications.
Identifiants
pubmed: 37745327
doi: 10.1101/2023.09.11.557100
pmc: PMC10515791
pii:
doi:
Types de publication
Preprint
Langues
eng
Subventions
Organisme : NIBIB NIH HHS
ID : R01 EB029483
Pays : United States
Organisme : NIBIB NIH HHS
ID : R01 EB032272
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS116302
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM119461
Pays : United States
Déclaration de conflit d'intérêts
Competing interests: The authors declare no competing interests.
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