A Functional Atlas of the Tardigrade Resistome Reveals a Diverse Molecular Toolkit for Extremotolerance

How organisms survive environmental extremes that push life to its physical limits is a fundamental question in biology. Tardigrades are a paradigm for this resilience, entering a state of suspended animation called cryptobiosis to withstand near-complete desiccation and intense radiation. While a few key effectors, including the DNA-shielding protein Dsup and various tardigrade-specific intrinsically disordered proteins (TDPs) have been identified, they constitute only a fraction of a vast, uncharacterized proteome, fundamentally limiting a systems-level understanding of this remarkable biology. Here we overcome this limitation by developing AEGIS, an AI-driven engine that systematically discovers and prioritizes novel ‘guardian’ proteins constituting the tardigrade molecular shield. Applying AEGIS to the tardigrade proteome, we construct the first functional atlas of the tardigrade ‘resistome’, revealing hundreds of novel protein families organized into a diverse and compartmentalized molecular toolkit. This atlas pinpoints new Dsup-like nuclear proteins, suggesting multi-layered genome protection, and a rich cohort of cytoplasmic proteins poised to form protective biological glasses. Our work provides a foundational resource for understanding the evolution of extremotolerance and serves as a blueprint for engineering novel biomolecules with transformative biotechnological potential.