IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage.
A single high dose of interferon-β (IFNβ) activates powerful cellular responses, in which many anti-viral, pro-apoptotic, and anti-proliferative proteins are highly expressed. Since some of these proteins are deleterious, cells downregulate this initial response rapidly. However, the expression of many anti-viral proteins that do no harm is sustained, prolonging a substantial part of the initial anti-viral response for days and also providing resistance to DNA damage. While the transcription factor ISGF3 (IRF9 and tyrosine-phosphorylated STATs 1 and 2) drives the first rapid response phase, the related factor un-phosphorylated ISGF3 (U-ISGF3), formed by IFNβ-induced high levels of IRF9 and STATs 1 and 2 without tyrosine phosphorylation, drives the second prolonged response. The U-ISGF3-induced anti-viral genes that show prolonged expression are driven by distinct IFN stimulated response elements (ISREs). Continuous exposure of cells to a low level of IFNβ, often seen in cancers, leads to steady-state increased expression of only the U-ISGF3-dependent proteins, with no sustained increase in other IFNβ-induced proteins, and to constitutive resistance to DNA damage.
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
HyeonJoo
H
Cheon
Elise G
EG
Holvey-Bates
John W
JW
Schoggins
Samuel
S
Forster
Paul
P
Hertzog
Naoko
N
Imanaka
Charles M
CM
Rice
Mark W
MW
Jackson
Damian J
DJ
Junk
George R
GR
Stark
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D060467:Disease Resistance / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics* / Q000378:metabolism; D016899:Interferon-beta / Q000494:pharmacology*; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D019139:Tumor Escape / Q000187:drug effects / Q000235:genetics; D014709:Vero Cells; D014777:Virus Diseases / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D014780:Viruses / Q000187:drug effects / Q000276:immunology / Q000472:pathogenicity
D000998:Antiviral Agents; C494227:IRF9 protein, human; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D016899:Interferon-beta