RNA



Basis for regulated RNA cleavage by functional analysis of RNase L and Ire1p


BEIHUA  DONG a1, MAHO  NIWA a2, PETER  WALTER a2 and ROBERT H.  SILVERMAN a1c1
a1 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
a2 Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California School of Medicine, San Francisco, California 94143, USA

Abstract

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.

(Received November 20 2000)
(Revised December 4 2000)
(Accepted December 15 2000)


Key Words: interferon; ribonuclease; RNA stability; unfolded protein response.

Correspondence:
c1 Reprint requests to: Robert H. Silverman, Department of Cancer Biology, NB40, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA; e-mail: silverr@ccf.org.