1. Mechanism of mda-5 Inhibition by paramyxovirus V proteins
- Author
-
Richard E. Randall, Kay Childs, J. Andrejeva, and Steve Goodbourn
- Subjects
Interferon-Induced Helicase, IFIH1 ,viruses ,Immunology ,Microbiology ,Cell Line ,DEAD-box RNA Helicases ,Viral Proteins ,Biopolymers ,Interferon ,Virology ,Two-Hybrid System Techniques ,Chlorocebus aethiops ,medicine ,Animals ,Humans ,Gene ,Vero Cells ,biology ,Hydrolysis ,Helicase ,RNA ,virus diseases ,biochemical phenomena, metabolism, and nutrition ,RNA Helicase A ,Molecular biology ,RNA silencing ,Mechanism of action ,Insect Science ,Paramyxoviridae ,biology.protein ,Vero cell ,Pathogenesis and Immunity ,medicine.symptom ,medicine.drug - Abstract
The RNA helicases encoded by melanoma differentiation-associated gene 5 (mda-5) and retinoic acid-inducible gene I (RIG-I) detect foreign cytoplasmic RNA molecules generated during the course of a virus infection, and their activation leads to induction of type I interferon synthesis. Paramyxoviruses limit the amount of interferon produced by infected cells through the action of their V protein, which binds to and inhibits mda-5. Here we show that activation of both mda-5 and RIG-I by double-stranded RNA (dsRNA) leads to the formation of homo-oligomers through self-association of the helicase domains. We identify a region within the helicase domain of mda-5 that is targeted by all paramyxovirus V proteins and demonstrate that they inhibit activation of mda-5 by blocking dsRNA binding and consequent self-association. In addition to this commonly targeted domain, some paramyxovirus V proteins target additional regions of mda-5. In contrast, V proteins cannot bind to RIG-I and consequently have no effect on the ability of RIG-I to bind dsRNA or to form oligomers.
- Published
- 2008