<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Role of LGP2 in\r\nthe Innate Immune System\r\nupon Viral Infections"^^ . "RIG-I-Iike receptors (RLRs) are a family of pattern recognition receptors that play an important\r\nrole in the induction of cellular antiviral responses. RLRs comprise LGP2, RIG-I and MDA5.\r\nThe latter two initiate antiviral signaling upon binding of viral cytoplasmic double-stranded (ds)\r\nRNA, resulting in the expression of interferons (IFNs) and IFN stimulated genes. LGP2\r\nenhances MDA5- and represses RIG-I-mediated signaling even though in the latter case the\r\nphysiological implication is less clear. Whether posttranslational modifications of LGP2 are\r\ninvolved in its diverse functions remains obscure.\r\nHepatitis delta virus (HDV), a small RNA virus with a circular genome, is an important human\r\npathogen responsible for the most severe form of viral hepatitis. HDV was shown to be sensed\r\nby MDA5 but the contribution of LGP2 to induction of the IFN response has not been explored.\r\nHence, the aim of my thesis work was (i) to gain a deeper understanding of the role of LGP2\r\nin regulating RLR signaling and (ii) to determine the contribution of LGP2 and its natural\r\npolymorphisms (encoding Q425R, N461S, R523Q) to sensing of HDV and other human viral\r\npathogens. Using knockout and overexpression systems, immunocompetent lung A549 and\r\nhepatic HepaRGNTCP cells were measured for their IFN response upon viral infection and\r\nsynthetic dsRNA stimulation. Mass spectrometry (MS) was performed to elucidate the impact\r\nof phosphorylation on the regulatory function of LGP2.\r\nStudies in A549 cells indicated faster RIG-I and delayed MDA5 signaling. LGP2 inhibited RIGI and strongly enhanced MDA5 signaling. RNA binding but not ATP hydrolysis was important\r\nfor both LGP2 functions upon synthetic dsRNA stimulation. In HDV infected HepaRGNTCP cells\r\nLGP2 was shown to directly bind HDV RNA. Moreover, LGP2 RNA binding and ATP hydrolysis\r\nfunction were essential to fully activate an IFN response that impaired HDV replication.\r\nMS identified S169, S365 and S464 as differentially regulated LGP2 phosphorylation sites.\r\nFollow-up functional assays revealed enhanced RIG-I inhibition by the phosphoablative S169A\r\nsubstitution in LGP2. Preliminary data with an S365A/S464D LGP2 double mutation,\r\nmimicking steady-state phosphorylation at those sites, indicated delayed responsiveness of\r\nthis LGP2 mutant towards HDV sensing.\r\nInvestigation of the Q425R, N461S and R523Q LGP2 variants identified Q425R LGP2, which\r\npredominates in the African population, as a gain-of-function version. Q425R LGP2 enhanced\r\nbasal and accelerated HDV-induced IFN signaling, thus lowering viral replication. This variant\r\nalso enhanced MDA5-mediated antiviral signaling upon severe acute respiratory syndrome\r\ncoronavirus type 2 infection. Mechanistically, Q425R LGP2 enhanced MDA5-RNA binding\r\ncompared to wild-type LGP2.\r\nIn conclusion, the results obtained during my thesis work broaden our understanding of the\r\nregulation of RLR signaling by LGP2. In the future, the gained knowledge might facilitate the\r\ndevelopment of new antiviral interventions by targeting RLRs for disease control."^^ . "2023" . . . . . . . "Nadine"^^ . "Gillich"^^ . "Nadine Gillich"^^ . . . . . . "Role of LGP2 in\r\nthe Innate Immune System\r\nupon Viral Infections (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Role of LGP2 in\r\nthe Innate Immune System\r\nupon Viral Infections (PDF)"^^ . . . "Dissertation Nadine Gillich.pdf"^^ . . . "Role of LGP2 in\r\nthe Innate Immune System\r\nupon Viral Infections (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Role of LGP2 in\r\nthe Innate Immune System\r\nupon Viral Infections (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Role of LGP2 in\r\nthe Innate Immune System\r\nupon Viral Infections (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Role of LGP2 in\r\nthe Innate Immune System\r\nupon Viral Infections (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #31208 \n\nRole of LGP2 in \nthe Innate Immune System \nupon Viral Infections\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .