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Abstract
Negative feedback can serve many different cellular functions, including noise reduction
in transcriptional networks and the creation of circadian oscillations. However, only
one special type of negative feedback ("integral feedback") ensures perfect adaptation,
where steady-state output is independent of steady-state input. Here we quantitatively
measure single-cell dynamics in the Saccharomyces cerevisiae hyperosmotic shock network,
which regulates membrane turgor pressure. Importantly, we find that the nuclear enrichment
of the MAP kinase Hog1 perfectly adapts to changes in external osmolarity, a feature
robust to signaling fidelity and operating with very low noise. By monitoring multiple
system quantities (e.g., cell volume, Hog1, glycerol) and using varied input waveforms
(e.g., steps and ramps), we assess in a minimally invasive manner the network location
of the mechanism responsible for perfect adaptation. We conclude that the system contains
only one effective integrating mechanism, which requires Hog1 kinase activity and
regulates glycerol synthesis but not leakage.