Hlx homeobox transcription factor negatively regulates interferon-gamma production in monokine-activated natural killer cells.
Natural killer (NK) cells contribute to host immunity, including tumor surveillance, through the production of interferon gamma (IFN-gamma). Although there is some knowledge about molecular mechanisms that induce IFN-gamma in NK cells, considerably less is known about the mechanisms that reduce its expression. Here, we investigate the role of the Hlx transcription factor in IFN-gamma production by NK cells. Hlx expression is induced in monokine-activated NK cells, but with delayed kinetics compared to IFN-gamma. Ectopic Hlx expression decreases IFN-gamma synthesis in primary human NK cells and IFN-gamma promoter activity in an NK-like cell line. Hlx protein levels inversely correlate with those of STAT4, a requisite factor for optimal IFN-gamma transcription. Mechanistically, we provide evidence indicating that Hlx overexpression accelerates dephosphorylation and proteasome-dependent degradation of the active Y693-phosphorylated form of STAT4. Thus, Hlx expression in activated NK cells temporally controls and limits the monokine-induced production of IFN-gamma, in part through the targeted depletion of STAT4.
Becknell
Brian
B
Medical Scientist Program, Department of Internal Medicine, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43210, USA.
Hughes
Tiffany L
TL
Freud
Aharon G
AG
Blaser
Bradley W
BW
Yu
Jianhua
J
Trotta
Rossana
R
Mao
Hsiaoyin C
HC
Caligiuri de Jesús
Marie L
ML
Alghothani
Mohamad
M
Benson
Don M
DM
Lehman
Amy
A
Jarjoura
David
D
Perrotti
Danilo
D
Bates
Michael D
MD
Caligiuri
Michael A
MA
D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D005801:Genes, Homeobox / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015846:Monokines / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C084058:HLX protein, human; C489999:Hlx protein, mouse; D018398:Homeodomain Proteins; D015846:Monokines; D050797:STAT4 Transcription Factor; D014157:Transcription Factors; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex