Acquired Stress Resistance Induced by Successive Stress Treatments: A Window Into Stress Physiology

In nature, cells experience stressful environmental changes in combination or succession, so the ability to prepare for impending stress is likely to provide a fitness advantage. Acquired stress resistance is a phenomenon observed from archaea to humans, in which cells exposed to a mild dose of stress become tolerant to a severe stress that might otherwise be lethal. Although initiation of the environmental stress response (ESR) had been proposed to underlie acquired stress tolerance, our previous results showed that ESR initiation could not fully explain the phenomenon. To identify the mechanism of acquired stress resistance, we used deep-sequencing and array-based analysis of the pooled HIP-HOP and DamP libraries to identify genes necessary for acquiring resistance to severe hydrogen peroxide (H2O2) stress following one of three different mild stress pretreatments (NaCl, DTT, and heat shock). Surprisingly, there was little overlap in the genes specifically required for acquisition of H2O2 tolerance after different mild-stress pretreatments. This indicates that acquired tolerance to the same severe stress occurred by distinctly different mechanisms following each mild-stress pretreatment. Integrative network analysis of protein-protein interactions, synthetic genetic interactions, and functional annotations revealed many new functional processes not previously linked to H2O2 tolerance, implicated upstream regulators activated by the pretreatments, and revealed new connections between functional processes important for the phenomenon. We present different models of acquired stress resistance to interpret the condition-specific involvement of genes. By studying stress tolerance in the context of sequential stress treatments and acquired stress resistance, we have tapped into a previously unexplored area of stress physiology.