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- Title
Cell-cycle-gated feedback control mediates desensitization to interferon stimulation.
- Authors
Mudla, Anusorn; Yanfei Jiang; Kei-ichiro Arimoto; Bingxian Xu; Rajesh, Adarsh; Ryan, Andy P.; Wei Wang; Daugherty, Matthew D.; Dong-Er Zhang; Nan Hao
- 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-a 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.
- Subjects
TYPE I interferons; DEUBIQUITINATING enzymes; INTERFERONS; CELL cycle; PEPTIDASE
- Publication
eLife, 2020, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.58825