Reciprocal inhibition between intracellular antiviral signaling and the RNAi machinery in mammalian cells.
RNA interference (RNAi) is an established antiviral defense mechanism in plants and invertebrates. Whether RNAi serves a similar function in mammalian cells remains unresolved. We find that in some cell types, mammalian RNAi activity is reduced shortly after viral infection via poly-ADP-ribosylation of the RNA-induced silencing complex (RISC), a core component of RNAi. Well-established antiviral signaling pathways, including RIG-I/MAVS and RNaseL, contribute to inhibition of RISC. In the absence of virus infection, microRNAs repress interferon-stimulated genes (ISGs) associated with cell death and proliferation, thus maintaining homeostasis. Upon detection of intracellular pathogen-associated molecular patterns, RISC activity decreases, contributing to increased expression of ISGs. Our results suggest that, unlike in lower eukaryotes, mammalian RISC is not antiviral in some contexts, but rather RISC has been co-opted to negatively regulate toxic host antiviral effectors via microRNAs.
The University of Texas at Austin, Molecular Genetics and Microbiology, 1 University Station A5000, Austin, TX 78712-0162, USA.
Gil Ju
GJ
Seo
Rodney P
RP
Kincaid
Teva
T
Phanaksri
James M
JM
Burke
Justin M
JM
Pare
Jennifer E
JE
Cox
Tien-Ying
TY
Hsiang
Robert M
RM
Krug
Christopher S
CS
Sullivan
D002460:Cell Line; D004267:DNA Viruses / Q000276:immunology*; D006801:Humans; D007372:Interferons / Q000276:immunology*; D008954:Models, Biological; D034622:RNA Interference; D012328:RNA Viruses / Q000276:immunology*; D034743:RNA-Induced Silencing Complex / Q000378:metabolism*; D015398:Signal Transduction
D034743:RNA-Induced Silencing Complex; D007372:Interferons