CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance.
The transcription factor STAT1 is important in natural killer (NK) cells, which provide immediate defense against tumor and virally infected cells. We show that mutation of a single phosphorylation site (Stat1-S727A) enhances NK cell cytotoxicity against a range of tumor cells, accompanied by increased expression of perforin and granzyme B. Stat1-S727A mice display significantly delayed disease onset in NK cell-surveilled tumor models including melanoma, leukemia, and metastasizing breast cancer. Constitutive phosphorylation of S727 depends on cyclin-dependent kinase 8 (CDK8). Inhibition of CDK8-mediated STAT1-S727 phosphorylation may thus represent a therapeutic strategy for stimulating NK cell-mediated tumor surveillance.
Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
Eva Maria
EM
Putz
Dagmar
D
Gotthardt
Gregor
G
Hoermann
Agnes
A
Csiszar
Silvia
S
Wirth
Angelika
A
Berger
Elisabeth
E
Straka
Doris
D
Rigler
Barbara
B
Wallner
Amanda M
AM
Jamieson
Winfried F
WF
Pickl
Eva Maria
EM
Zebedin-Brandl
Mathias
M
Müller
Thomas
T
Decker
Veronika
V
Sexl
D000818:Animals; D045744:Cell Line, Tumor; D056850:Cyclin-Dependent Kinase 8 / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D005260:Female; D007157:Immunologic Surveillance; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D007942:Leukemia, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C524803:Cdk8 protein, mouse; D056850:Cyclin-Dependent Kinase 8