Stochastic dynamics of Type-I interferon responses.
Journal
PLoS computational biology
ISSN: 1553-7358
Titre abrégé: PLoS Comput Biol
Pays: United States
ID NLM: 101238922
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
13
04
2022
accepted:
30
09
2022
revised:
02
11
2022
pubmed:
22
10
2022
medline:
5
11
2022
entrez:
21
10
2022
Statut:
epublish
Résumé
Interferon (IFN) activates the transcription of several hundred of IFN stimulated genes (ISGs) that constitute a highly effective antiviral defense program. Cell-to-cell variability in the induction of ISGs is well documented, but its source and effects are not completely understood. The molecular mechanisms behind this heterogeneity have been related to randomness in molecular events taking place during the JAK-STAT signaling pathway. Here, we study the sources of variability in the induction of the IFN-alpha response by using MxA and IFIT1 activation as read-out. To this end, we integrate time-resolved flow cytometry data and stochastic modeling of the JAK-STAT signaling pathway. The complexity of the IFN response was matched by fitting probability distributions to time-course flow cytometry snapshots. Both, experimental data and simulations confirmed that the MxA and IFIT1 induction circuits generate graded responses rather than all-or-none responses. Subsequently, we quantify the size of the intrinsic variability at different steps in the pathway. We found that stochastic effects are transiently strong during the ligand-receptor activation steps and the formation of the ISGF3 complex, but negligible for the final induction of the studied ISGs. We conclude that the JAK-STAT signaling pathway is a robust biological circuit that efficiently transmits information under stochastic environments.
Identifiants
pubmed: 36269758
doi: 10.1371/journal.pcbi.1010623
pii: PCOMPBIOL-D-22-00587
pmc: PMC9629604
doi:
Substances chimiques
Interferon Type I
0
Interferon-alpha
0
Antiviral Agents
0
STAT1 Transcription Factor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1010623Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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