Intrinsic cellular-based defense mechanisms have been recently discovered as an essential component of immunity, involved in the capacity of cells to resist pathogens. However, unlike the innate and adaptive branches of the immune system, intrinsic immune defenses are mediated by cellular restriction factors that are constitutively expressed and active even before a pathogen enters the cell. The interferon inducible protein IFI16, a member of the HIN-200 family, displays a multifaceted activity, mainly antiproliferative and proinflammatory. Recently, it has been also demonstrated its role as intracellular sensor of foreign DNA. Human Cytomegalovirus (HCMV) is a b-Herpesvirus that commonly and persistently infects humans. Viral gene expression in HCMV undergoes sequential regulation, which leads to the occurrence of induction and repression cycles in the immediate early (IE), early (E), and late (L) phases of viral replication. Previous results obtained by our group demonstrated that overexpression of IFI16 inhibited transcription of HCMV early and late genes and down-regulated viral replication. However, HCMV infection of human fibroblasts (HELFs) induced the upregulation of IFI16 protein as early as 48 hours post infection, that continued to increase until 96 hours post infection and disappeared thereafter. In addition, HCMV infection was able to modify IFI16 nuclear localization. A confocal double-labeling indirect immunofluorescence assay showed that at 48 h post-infection, IFI16 progressively exited the nucleus and colocalized with HCMV gB in the assembly complex which consists of multivesicular bodies (MVBs). Collectively, these findings may reflect the mechanism used by HCMV to evade the antiviral function of IFI16.
Human Cytomegalovirus induces redistribution of the interferon inducible protein IFI16 from nucleus to cytoplasm
GATTI, DEBORAH;DELL'OSTE, Valentina;LUGANINI, ANNA;DE ANDREA, Marco;GRIBAUDO, Giorgio;LANDOLFO, Santo Giuseppe
2011-01-01
Abstract
Intrinsic cellular-based defense mechanisms have been recently discovered as an essential component of immunity, involved in the capacity of cells to resist pathogens. However, unlike the innate and adaptive branches of the immune system, intrinsic immune defenses are mediated by cellular restriction factors that are constitutively expressed and active even before a pathogen enters the cell. The interferon inducible protein IFI16, a member of the HIN-200 family, displays a multifaceted activity, mainly antiproliferative and proinflammatory. Recently, it has been also demonstrated its role as intracellular sensor of foreign DNA. Human Cytomegalovirus (HCMV) is a b-Herpesvirus that commonly and persistently infects humans. Viral gene expression in HCMV undergoes sequential regulation, which leads to the occurrence of induction and repression cycles in the immediate early (IE), early (E), and late (L) phases of viral replication. Previous results obtained by our group demonstrated that overexpression of IFI16 inhibited transcription of HCMV early and late genes and down-regulated viral replication. However, HCMV infection of human fibroblasts (HELFs) induced the upregulation of IFI16 protein as early as 48 hours post infection, that continued to increase until 96 hours post infection and disappeared thereafter. In addition, HCMV infection was able to modify IFI16 nuclear localization. A confocal double-labeling indirect immunofluorescence assay showed that at 48 h post-infection, IFI16 progressively exited the nucleus and colocalized with HCMV gB in the assembly complex which consists of multivesicular bodies (MVBs). Collectively, these findings may reflect the mechanism used by HCMV to evade the antiviral function of IFI16.
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