Proteasomal degradation of herpes simplex virus capsids in macrophages releases DNA to the cytosol for recognition by DNA sensors.
The innate immune system is important for control of infections, including herpesvirus infections. Intracellular DNA potently stimulates antiviral IFN responses. It is known that plasmacytoid dendritic cells sense herpesvirus DNA in endosomes via TLR9 and that nonimmune tissue cells can sense herpesvirus DNA in the nucleus. However, it remains unknown how and where myeloid cells, such as macrophages and conventional dendritic cells, detect infections with herpesviruses. In this study, we demonstrate that the HSV-1 capsid was ubiquitinated in the cytosol and degraded by the proteasome, hence releasing genomic DNA into the cytoplasm for detection by DNA sensors. In this context, the DNA sensor IFN-γ-inducible 16 is important for induction of IFN-β in human macrophages postinfection with HSV-1 and CMV. Viral DNA localized to the same cytoplasmic regions as did IFN-γ-inducible 16, with DNA sensing being independent of viral nuclear entry. Thus, proteasomal degradation of herpesvirus capsids releases DNA to the cytoplasm for recognition by DNA sensors.
Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
Kristy A
KA
Horan
Kathrine
K
Hansen
Martin R
MR
Jakobsen
Christian K
CK
Holm
Stine
S
Søby
Leonie
L
Unterholzner
Mikayla
M
Thompson
John A
JA
West
Marie B
MB
Iversen
Simon B
SB
Rasmussen
Svend
S
Ellermann-Eriksen
Evelyn
E
Kurt-Jones
Santo
S
Landolfo
Blossom
B
Damania
Jesper
J
Melchjorsen
Andrew G
AG
Bowie
Katherine A
KA
Fitzgerald
Søren R
SR
Paludan
D000818:Animals; D002213:Capsid / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics* / Q000276:immunology; D003713:Dendritic Cells / Q000378:metabolism / Q000821:virology; D020868:Gene Silencing; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis / Q000276:immunology; D008264:Macrophages / Q000378:metabolism* / Q000821:virology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D054875:Ubiquitination; D014709:Vero Cells
D004279:DNA, Viral; D009687:Nuclear Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C076700:IFI16 protein, human; D016899:Interferon-beta; D046988:Proteasome Endopeptidase Complex