Figure 4. Mechanism of acquisition of tolerance to stress.

(A) Mean cell growth rate (top panel) of cells exposed to H₂O₂ steps of the magnitude indicated in the bottom panel at t = 400 min after a 0.2 mM pretreatment at t = 0 min. (B) Fraction of cells without permanent growth arrest at different concentrations of H₂O₂ in the presence (yellow) or absence (blue) of pretreatment. N = 100 for each concentration. (C) Response of the linear system to simple H₂O₂ step of amplitude ΔI = 0.6 mM for naive (magenta: I₀ = 0 mM) or pretreated (bleu: I₀ = 0.2 mM) cells. (D) Top: Mean cell transcriptional dynamics (top panel) of the TRX2 promoter (Trx2-sfGFP-degron) for the H₂O₂ treatments shown in the middle panel. Bottom: Quantification of the maximum transcription rate of the TRX2 promoter during the indicated steps. Two-means Z test. (E) Mean cell Yap1-GFP nuclear localization upon a 0.2 mM H₂O₂ step for cells with (green line) or without (magenta line) a 0.2 mM pretreatment, as indicated in the bottom panel. (F) Quantification of the amplitude of the burst in Yap1 nuclear localization during a 0.1 mM H₂O₂ challenge step. The lines indicate the fit of the linear (red) and nonlinear (magenta) models. (G) Numerical phase diagram indicating the region in which adaptation is permitted as a function of the overall stress magnitude ΔI and stress rate δ for the linear (left) and nonlinear (right) models. The solid black line indicates the contour given when H_max = H_tox (survival threshold) as in Figure 3C. The vertical dashed line represents the basal stress resistance, as observed in step experiments. The green color represents the region in which cells can be trained to resist higher stress levels through a slow ramping process. The magenta region highlights the shift in survival threshold obtained following a pretreatment according to the nonlinear model. A, D–F, error bars and shaded regions are SEM (N > 100 for most time points). B, error bars are 95% CI. See also Figure 4—figure supplement 1.

DOI: http://dx.doi.org/10.7554/eLife.23971.018

Figure 4—figure supplement 1. Acquisition of tolerance: comparison of the linear and nonlinear models.

(A) The mean cellular intensity of the phase-contrast highest decile is quantified for a population of cells exposed to critical ΔI = 1 mM (black line) after pretreatment of I₀ = 0.2 mM and for control population of cells only exposed to the pretreatment of I₀ = 0.2 mM (magenta line). (B–C) Same as Figure 4A–B, but with the yap1Δ mutant. (D) Same as Figure 4E, but with various levels of H₂O₂ during pretreatment and with a challenging step of ΔI = 0.1 mM H₂O₂. The Yap1 maximal amplitudes from this graph are represented in Figure 4F. (E) Numerical simulation of the response of the H₂O₂ homeostatic machinery to a sequence of two consecutive stress steps of indicated amplitude (top), using the linear feedback model. The first step (I₀) corresponds to the pre-treatment, while the second represents the challenging step (ΔI) described in Figure 4. Each colored line corresponds to a particular temporal profile of H₂O₂ concentration. H (Middle) and A (Bottom) are two variables of the model described in Figure 3 and Materials and methods. (F) Same as (E), but for the nonlinear feedback model. (A,B,D) Error bars and shaded regions are SEM (N > 100 for most time points). (C) error bars are 95% CI.

DOI: http://dx.doi.org/10.7554/eLife.23971.019