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Cell-cycle-gated feedback control mediates desensitization to interferon stimulation

Anusorn Mudla1, Yanfei Jiang1, Kei-Ichiro Arimoto1

  • 1Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States.

Elife
|September 18, 2020
PubMed

Insights

Type I interferon (IFN) stimulation duration dictates cellular response, causing either priming or desensitization. This effect is controlled by a molecular network involving ubiquitin-specific peptidase 18 (USP18) and cell cycle phase.

Area of Science:

  • Cellular and Molecular Biology
  • Immunology
  • Systems Biology

Background:

  • Cells process external signals like cytokines through molecular circuits.
  • Temporal variations in extracellular cues influence cellular responses.
  • Type I interferons (IFNs) are critical cytokines involved in immune responses.

Purpose of the Study:

  • To investigate the regulatory network of type I interferon (IFN) response in single human cells.
  • To understand how cells process repetitive IFN stimulation with varying input durations.
  • To elucidate the mechanisms behind IFN-induced priming versus desensitization.

Main Methods:

  • Integration of microfluidics for precise stimulus control.
  • Time-lapse microscopy for observing cellular dynamics.
  • Computational modeling to analyze regulatory network behavior.

Main Results:

  • IFN-α pretreatment duration determines cellular response: priming or desensitization.
  • A regulatory network with fast positive and delayed negative feedback loops, mediated by USP18 upregulation, governs these responses.
  • USP18 upregulation is initiated only during G1/early S phases, leading to heterogeneous and delayed induction kinetics in single cells.

Conclusions:

  • Cell cycle gating of USP18 upregulation enables duration-dependent desensitization to repetitive IFN stimulations.
  • Temporal compartmentalization of feedback loops allows for context-dependent cellular responses.
  • The study reveals a sophisticated mechanism for processing dynamic extracellular signals.

Keywords:
computational biologycomputational modelingdesensitizationhumaninterferonssignal dynamicssingle-cell analysissystems biologytime-lapse microscopy

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