Virus-activated interferon regulatory factor 7 upregulates expression of the interferon-regulated BST2 gene independently of interferon signaling.
BST-2/tetherin is an interferon (IFN)-inducible host restriction factor that inhibits the release of many enveloped viruses and functions as a negative-feedback regulator of IFN production by plasmacytoid dendritic cells. Currently, mechanisms underlying BST2 transcriptional regulation by type I IFN remain largely unknown. Here, we demonstrate that the BST2 promoter is a secondary target of the IFN cascade and show that a single IRF binding site is sufficient to render this promoter responsive to IFN-α. Interestingly, expression of IRF-1 or virus-activated forms of IRF-3 and IRF-7 stimulated the BST2 promoter even under conditions where type I IFN signaling was inhibited. Indeed, vesicular stomatitis virus could directly upregulate BST-2 during infection of mouse embryonic fibroblasts through a process that required IRF-7 but was independent from the type I IFN cascade; however, in order to achieve optimal BST-2 induction, the type I IFN cascade needed to be engaged through activation of IRF-3. Furthermore, using human peripheral blood mononuclear cells, we show that BST-2 upregulation is part of an early intrinsic immune response since TLR8 and TLR3 agonists, known to trigger pathways that mediate activation of IRF proteins, could upregulate BST-2 prior to engagement of the type I IFN pathway. Collectively, our findings reveal that BST2 is activated by the same signals that trigger type I IFN production, outlining a regulatory mechanism ensuring that production of type I IFN and expression of a host restriction factor involved in the IFN negative-feedback loop are closely coordinated.
Laboratory of Human Retrovirology, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada.
Mariana G
MG
Bego
Johanne
J
Mercier
Eric A
EA
Cohen
D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000235:genetics* / Q000378:metabolism; D007372:Interferons / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D015533:Transcriptional Activation; D015854:Up-Regulation; D054243:Vesicular Stomatitis / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000502:physiology*; D000074010:Bone Marrow Stromal Antigen 2
D015703:Antigens, CD; D058851:GPI-Linked Proteins; D050839:Interferon Regulatory Factor-7; D007372:Interferons; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2