[Frontiers in Bioscience S4, 767-786, January 1, 2012]

Pathologic effects of RNase-L dysregulation in immunity and proliferative control

Heather J. Ezelle1,2, Bret A. Hassel1-3

1Department of Microbiology and Immunology, 2Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore MD, 3Research Services, Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201 USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. The 2-5A System
3.1. Anatomy and regulation of the 2-5A system
3.2. Molecular mechanisms of RNase-L action
3.2.1. RNA targets and consequences of RNase-L cleavage
3.2.2. Protein-protein interactions
3.2.2.1. RLI
3.2.2.2. eRF3
3.2.2.3. IF2mt
3.2.2.4. Androgen receptor
3.2.2.5. IQGAP1
4. Biologic roles for RNase-L and disease-associated alterations in its activity
4.1. Antiviral functions
4.1.1. Picornaviruses
4.1.2. HCV
4.1.3. West Nile Virus
4.1.4. HIV
4.1.5. Influenza
4.2. A role for RNase-L in cancer
4.3. Immunomodulatory activities
4.3.1. Antibacterial and proinflammatory functions
4.3.2. Association with Chronic Fatigue Syndrome
5. Conclusions and therapeutic implications
6. Acknowledgements
7. References

1. ABSTRACT

The endoribonuclease RNase-L is the terminal component of an RNA cleavage pathway that mediates antiviral, antiproliferative and immunomodulatory activities. Inactivation or dysregulation of RNase-L is associated with a compromised immune response and increased risk of cancer, accordingly its activity is tightly controlled and requires an allosteric activator, 2',5'-linked oligoadenylates, for enzymatic activity. The biological activities of RNase-L are a result of direct and indirect effects of RNA cleavage and microarray analyses have revealed that RNase-L impacts the gene expression program at multiple levels. The identification of RNase-L-regulated RNAs has provided insights into potential mechanisms by which it exerts antiproliferative, proapoptotic, senescence-inducing and innate immune activities. RNase-L protein interactors have been identified that serve regulatory functions and are implicated as alternate mechanisms of its biologic functions. Thus while the molecular details are understood for only a subset of RNase-L activities, its regulation by small molecules and critical roles in host defense and as a candidate tumor suppressor make it a promising therapeutic target.