title: LGP2 downregulates interferon production during infection with seasonal human influenza A viruses that activate interferon regulatory factor 3.
abstract: LGP2, a member of the RIG-I-like receptor family, lacks the amino-terminal caspase activation recruitment domains (CARDs) required for initiating the activation of interferon regulatory factor 3 (IRF3) and interferon (IFN) transcription. The role of LGP2 in virus infection is controversial, and the only LGP2 experiments previously carried out with mammalian influenza A viruses employed an attenuated, mouse-adapted H1N1 A/PR/8/34 (PR8) virus that does not encode the NS1 protein. Here we determine whether LGP2 has a role during infection with wild-type, nonattenuated influenza A viruses that have circulated in the human population, specifically two types of seasonal influenza A viruses: (i) H3N2 and H1N1 viruses that activate IRF3 and IFN transcription and (ii) recent H1N1 viruses that block these two activations. In human cells infected with an H3N2 virus that activates IRF3, overexpression of LGP2 or its repressor domain decreased STAT1 activation and IFN-β transcription approximately 10-fold. Overexpression of LGP2 also caused a 10-fold decrease of STAT1 activation during infection with other seasonal influenza A viruses that activate IRF3. Using LGP2(+/+) and LGP2(-/-) mouse cells, we show that endogenous LGP2 decreased IFN production during H3N2 virus infection 3- to 4-fold. In contrast, in both mouse and human cells infected with H1N1 viruses that do not activate IRF3, LGP2 had no detectable role. These results demonstrate that LGP2 downregulates IFN production during infection by seasonal influenza A viruses that activate IRF3 and IFN transcription. It is intriguing that LGP2, a host protein induced during influenza A virus infection, downregulates the host antiviral IFN response.
authors: Department of Molecular Genetics and Microbiology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas, USA.
authors: Meghana
authors: M
authors: Malur
authors: Michael
authors: M
authors: Gale
authors: Robert M
authors: RM
authors: Krug
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004285:Dogs; D015536:Down-Regulation; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000378:metabolism; D009980:Influenza A virus / Q000378:metabolism*; D007251:Influenza, Human / Q000378:metabolism / Q000821:virology; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020365:RNA Helicases / Q000235:genetics / Q000502:physiology*
chemical_list: D050838:Interferon Regulatory Factor-3; C520569:DHX58 protein, human; D020365:RNA Helicases