Cytokine-independent induction of LGP2/DHX58 in viral infection.

Laboratory of genetics and physiology 2 (LGP2, also known as DHX58) is unique among members of the RIG-I-like receptor (RLR) family as it lacks the caspase activation and recruitment domain. Although LGP2 per se cannot directly activate downstream antiviral signalling, it plays important regulatory roles, primarily by modulating innate immune responses mediated by RIG-I and MDA5. However, the detailed mechanisms by which LGP2 is induced in mammalian cells during viral infection remain incompletely understood. Herein, we show that LGP2 is strongly upregulated by dsRNA stimulation or virus infection in cultured human cell lines via TLR3 and RLRs, respectively, and that substantial induction of LGP2 remains when paracrine/autocrine signalling of IFNs and/or inflammatory cytokines is abrogated by genetic deletion or chemical inhibition. The latter observation is in stark contrast to the case of myxovirus resistance proteins, the induction of which is strictly IFN-dependent. Mechanistically, we found LGP2 expression to be upregulated by ectopic expression of IRF3-5D, a phospho-mimetic mutant of activated IRF3, or to a lesser extent, by overexpression of RELA, the p65 subunit of NFκB, in an IFN-independent fashion. Additionally, we demonstrated that this regulation operated transcriptionally at the