Many
organisms can survive extreme conditions and successfully
recover to normal life. This extremotolerant behavior has been attributed
in part to repetitive, amphipathic, and intrinsically disordered proteins
that are upregulated in the protected state. Here, we assemble a library
of approximately 300 naturally occurring and designed extremotolerance-associated
proteins to assess their ability to protect human cells from chemically
induced apoptosis. We show that several proteins from tardigrades,
nematodes, and the Chinese giant salamander are apoptosis-protective.
Notably, we identify a region of the human ApoE protein with similarity
to extremotolerance-associated proteins that also protects against
apoptosis. This region mirrors the phase separation behavior seen
with such proteins, like the tardigrade protein CAHS2. Moreover, we
identify a synthetic protein, DHR81, that shares this combination
of elevated phase separation propensity and apoptosis protection.
Finally, we demonstrate that driving protective proteins into the
condensate state increases apoptosis protection, and highlights the
ability of DHR81 condensates to sequester caspase-7. Taken together,
this work draws a link between extremotolerance-associated proteins,
condensate formation, and designing human cellular protection.