title: NSP1 of human rotaviruses commonly inhibits NF-κB signalling by inducing β-TrCP degradation.
abstract: Rotavirus is a leading cause of severe gastroenteritis in infants worldwide. Rotavirus nonstructural protein 1 (NSP1) is a virulence factor that inhibits innate host immune responses. NSP1 from some rotaviruses targets host interferon response factors (IRFs), leading to inhibition of type I interferon expression. A few rotaviruses encode an NSP1 that inhibits the NF-κB pathway by targeting β-TrCP, a protein required for IκB degradation and NF-κB activation. Available evidence suggests that these NSP1 properties involve proteosomal degradation of target proteins. We show here that NSP1 from several human rotaviruses and porcine rotavirus CRW-8 inhibits the NF-κB pathway, but cannot degrade IRF3. Furthermore, β-TrCP levels were much reduced in cells infected with these rotaviruses. This provides strong evidence that β-TrCP degradation is required for NF-κB pathway inhibition by NSP1 and demonstrates the relevance of β-TrCP degradation to rotavirus infection. C-terminal regions of NSP1, including a serine-containing motif resembling the β-TrCP recognition motif of IκB, were required for NF-κB inhibition. CRW-8 infection of HT-29 intestinal epithelial cells induced significant levels of IFN-β and CCL5 but not IL-8. This contrasts with monkey rotavirus SA11-4F, whose NSP1 inhibits IRF3 but not NF-κB. Substantial amounts of IL-8 but not IFN-β or CCL5 were secreted from HT-29 cells infected with SA11-4F. Our results show that human rotaviruses commonly inhibit the NF-κB pathway by degrading β-TrCP and thus stabilizing IκB. They suggest that NSP1 plays an important role during human rotavirus infection by inhibiting the expression of NF-κB-dependent cytokines, such as IL-8.
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia.
authors.forename: Izabel J M
authors.initials: IJ
authors.lastname: Di Fiore
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Pane
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia.
authors.forename: Gavan
authors.initials: G
authors.lastname: Holloway
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Coulson
mesh_terms: D000818:Animals; D002460:Cell Line; D004847:Epithelial Cells / Q000276:immunology / Q000821:virology; D006801:Humans; D057131:Immune Evasion; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D059748:Proteolysis; D012401:Rotavirus / Q000276:immunology*; D013552:Swine; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000037:antagonists & inhibitors*
chemical_list: D016328:NF-kappa B; D017361:Viral Nonstructural Proteins; D044844:beta-Transducin Repeat-Containing Proteins; C104282:nsp1 protein, Rotavirus