Abstract
Tardigrades are microscopic animals renowned for their ability to survive extreme desiccation. Unlike many desiccation-tolerant organisms that accumulate high levels of the disaccharide trehalose to protect themselves during drying, tardigrades accumulate little or undetectable levels. Using comparative metabolomics, we find that despite being enriched at low levels, trehalose is a key biomarker distinguishing hydration states of tardigrades. In vitro, naturally occurring stoichiometries of trehalose and CAHS proteins, intrinsically disordered proteins with known protective capabilities, were found to produce synergistic protective effects during desiccation. In vivo, this synergistic interaction is required for robust CAHS-mediated protection. This demonstrates that trehalose acts not only as a protectant, but also as a synergistic cosolute. Beyond desiccation tolerance, our study provides insights into how the solution environment tunes intrinsically disordered proteins' functions, many of which are vital in biological contexts such as development and disease that are concomitant with large changes in intracellular chemistry.