Abstract:
:Cells use molecular circuits to interpret and respond to extracellular cues, such as hormones and cytokines, which are often released in a temporally varying fashion. In this study, we combine microfluidics, time-lapse microscopy, and computational modeling to investigate how the type I interferon (IFN)-responsive regulatory network operates in single human cells to process repetitive IFN stimulation. We found that IFN-α pretreatments lead to opposite effects, priming versus desensitization, depending on input durations. These effects are governed by a regulatory network composed of a fast-acting positive feedback loop and a delayed negative feedback loop, mediated by upregulation of ubiquitin-specific peptidase 18 (USP18). We further revealed that USP18 upregulation can only be initiated at the G1/early S phases of cell cycle upon the treatment onset, resulting in heterogeneous and delayed induction kinetics in single cells. This cell cycle gating provides a temporal compartmentalization of feedback loops, enabling duration-dependent desensitization to repetitive stimulations.
journal_name
Elifejournal_title
eLifeauthors
Mudla A,Jiang Y,Arimoto KI,Xu B,Rajesh A,Ryan AP,Wang W,Daugherty MD,Zhang DE,Hao Ndoi
10.7554/eLife.58825subject
Has Abstractpub_date
2020-09-18 00:00:00issn
2050-084Xpii
58825journal_volume
9pub_type
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