Mechanism of mda-5 Inhibition by paramyxovirus V proteins.
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.
Childs
K S
KS
Division of Basic Medical Sciences, St. George's, University of London, London SW17 0RE, United Kingdom.
Andrejeva
J
J
Randall
R E
RE
Goodbourn
S
S
D000818:Animals; D001704:Biopolymers; D002460:Cell Line; D002522:Chlorocebus aethiops; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D000072640:Interferon-Induced Helicase, IFIH1; D010252:Paramyxoviridae / Q000502:physiology*; D020798:Two-Hybrid System Techniques; D014709:Vero Cells; D014764:Viral Proteins / Q000502:physiology*
D001704:Biopolymers; D014764:Viral Proteins; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1