Innate immune activation by HCV RNA. A) RIG-I binds to PAMPs in HCV RNA
and changes its conformation, activating one or more E3 ubiquitin ligases
(yellow shapes). Ubiquitinated RIG-I may activate MAVS, which then forms
prion-like aggregates that recruit additional ubiquitin ligases. Recent evidence
suggests that MAVS on peroxisomes is particularly important for induction of
IFNλ. Subsequent ubiquitination steps stimulate recruitment of enzymes
that activate the downstream IRF3 and NFκB pathways. HCV’s
NS3/4A protease can disable this pathway by cleaving MAVS near its transmembrane
domain. B) TLR3 recognizes dsRNA within endosomal compartments, signaling via
the adaptor, TRIF. TRIF stimulates ubiquitin-conjugating enzymes, resulting in
recruitment of enzymes that activate the IRF3 and NFκB transcription
factors. HCV’s NS3-4A protease can disable TLR3 signaling by cleaving
TRIF.