To prevent RNA virus–dependent tissue damage caused by interferon-regulatory factor 3 (IRF3)–induced type I interferons, proteasome-dependent destruction of IRF3 is orchestrated by the cytoplasmic prolyl isomerase Pin1.
Successful host defense against virus infection relies on the rapid production of type I interferons (IFN-) and the subsequent transcription of hundreds of interferon-stimulated genes, which leads to a cellular antiviral state and prevents viral replication. Production of IFN- is one of the earliest responses induced by virus replication intermediates, such as double-stranded RNA (dsRNA), which are 'sensed' by germline-encoded pattern-recognition receptors. Two distinct classes of dsRNA sensors have been linked to the regulation of IFN-. Toll-like receptor 3 (TLR3) and the RNA helicases RIG-I and Mda-5 detect dsRNA and trigger signal transduction cascades that culminate in the formation of a multiprotein complex of transcription factors, which contains ATF-2–c-Jun, transcription factor NF-kB, interferon-regulatory factor 3 (IRF3) and IRF7. Assembly of this 'enhanceosome' on the IFN- enhancer leads to IFN- production. Although critical for protection of the host, the production of IFN- must also be tightly controlled to maintain homeostasis and prevent tissue damage. Although considerable progress has been made in the understanding of the molecular mechanisms underlying the induction of IFN-, how those mechanisms are switched off is not well understood. Lgp2, an RNA helicase related to RIG-I, has been shown to function in a negative feedback loop as a postinduction inhibitor of antiviral responses. In this issue of Nature Immunology, Yamaoka and colleagues indicate involvement of a different negative regulatory mechanism, via the cytoplasmic prolyl isomerase Pin1, in control of both TLR3- and RIG-I-mediated antiviral responses.
