Interferon-induced STAT1 (signal transducer and activator of transcription 1) signal transduction constitutes a dynamic network of concurrent activation and inactivation steps that directly transmits extracellular information from the plasma membrane to the nucleus. To elucidate how nuclear retention of tyrosine-phosphorylated STAT1 as a fundamental principle of the STAT1 network directs signal transduction, we have developed a mathematical rate equation model for STAT1 nucleocytoplasmic shuttling. Based on an interplay between experimental data on the behavior of transport variants with altered nucleocytoplasmic translocation and computational simulations, we calculated the mean residence time of phosphorylated STAT1 in the nucleus to be 13.1 min (5%–95%-CI = 1.6–48.4 min), indicating the highly dynamic nature of the STAT1 signal network. However, when we assessed the time course of unphosphorylated STAT1 from nuclear entry to its subsequent cytoplasmic exit, we found that the half-life of nuclear STAT1 in resting cells was even shorter (5.0 min, 5%–95%-CI = 0.3–15.0 min). Our data reveal that the STAT1 pathway has not evolved to achieve maximal signal amplification, but rather allows for a compromise between rapid termination and efficient signal output. Decoupling of nuclear export from its prior dephosphorylation in a way that also phospho-STAT1 can unphysiologically exit the nucleus results in an overall lower nuclear concentration of activated STAT1 throughout the entire stimulation period, demonstrating the physiological significance of the nuclear export block of phosphorylated STAT1 for cytokine-driven signal propagation. Thus, the complex dynamics of the unique STAT1 network accounts for both efficient and flexible signal transduction particularly in the course of transient stimulation. • Based on experimental data obtained using STAT1 mutants with altered nucleocytoplasmic translocation together with computational simulations, the mean residence time of phosphorylated STAT1 in the nucleus was calculated to be 13.1 min (5%–95% confidence interval CI = 1.6–48.4 min). • The half-life of nuclear STAT1 in resting cells was even shorter (5.0 min, 5%–95% CI = 0.3–15.0 min), underscoring the highly dynamic nature of the STAT1 signaling network in cytokine-stimulated cells. • The STAT1 pathway is not optimized for maximal signal amplification; instead, it represents a balance between rapid signal termination and efficient signal output. • Decoupling nuclear export from prior dephosphorylation leads to an overall lower nuclear concentration of activated STAT1 during the entire stimulation period, illustrating the physiological importance of blocking nuclear export of phosphorylated STAT1 for effective cytokine-driven signal propagation. • Thus, the pathway operates below its maximum possible signal propagation capacity. The complex dynamics inherent to the STAT1 network allow for both efficient and adaptable signal transduction, particularly at low activation levels.
Meyer et al. (Sun,) studied this question.