RNase L and Ire1p are members of a superfamily of
regulated endoribonucleases that play essential roles
in mediating diverse types of cellular stress responses.
2′-5′ oligoadenylates, produced in response
to interferon treatment and viral double-stranded RNA,
are necessary to activate RNase L. In contrast, unfolded
proteins in the endoplasmic reticulum activate Ire1p, a
transmembrane serine/threonine kinase and endoribonuclease.
To probe their similarities and differences, molecular
properties of wild-type and mutant forms of human RNase
L and yeast Ire1p were compared. Surprisingly, RNase L
and Ire1p showed mutually exclusive RNA substrate specificity
and partially overlapping but not identical requirements
for phylogenetically conserved amino acid residues in their
nuclease domains. A functional model for RNase L was generated
based on the comparative analysis with Ire1p that assigns
novel roles for ankyrin repeats and kinase-like domains.