Novel antiviral host factor, TNK1, regulates IFN signaling through serine phosphorylation of STAT1.
In response to viral infection, the host induces over 300 IFN-stimulated genes (ISGs), which are the central component of intracellular antiviral innate immunity. Inefficient induction of ISGs contributes to poor control and persistence of hepatitis C virus infection. Therefore, further understanding of the hepatocytic ISG regulation machinery will guide us to an improved management strategy against hepatitis C virus infection. In this study, comprehensive genome-wide, high-throughput cDNA screening for genes regulating ISG expression identified a tyrosine kinase nonreceptor 1 (TNK1) as a unique player in the ISG induction pathway. The immune-modulatory function of TNK1 has never been studied, and this study characterizes its significance in antiviral innate immunity. TNK1 is abundantly expressed in hepatocytes and maintains basal ISG expression. More importantly, TNK1 plays a critical role in type I IFN-mediated ISG induction. We discovered that the activated IFN receptor complex recruits TNK1 from the cytoplasm. TNK1 is then phosphorylated to enhance its kinase activity. The activated TNK1 potentiates JAK-STAT signaling through dual phosphorylation of STAT1 at tyrosine 701 and serine 727 amino acid positions. Our loss-of-function approach demonstrated that TNK1 governs a cluster of ISG expression that defines the TNK1 pathway effector genes. More importantly, TNK1 abundance is inversely correlated to viral replication efficiency and is also a determinant factor for the hepatocytic response to antiviral treatment. Taken together, our studies found a critical but unidentified integrated component of the IFN-JAK-STAT signaling cascade.
Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
Ee Lyn
EL
Ooi
Stephanie T
ST
Chan
Noell E
NE
Cho
Courtney
C
Wilkins
Jessica
J
Woodward
Meng
M
Li
Ushio
U
Kikkawa
Timothy
T
Tellinghuisen
Michael
M
Gale
Takeshi
T
Saito
D000818:Animals; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000235:genetics; D004198:Disease Susceptibility; D005326:Fetal Proteins / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005820:Genetic Testing; D015894:Genome, Human / Q000235:genetics; D016174:Hepacivirus / Q000502:physiology; D006526:Hepatitis C / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000821:virology; D022781:Hepatocytes / Q000201:enzymology / Q000473:pathology / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007372:Interferons / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
D018076:DNA, Complementary; D005326:Fetal Proteins; D050794:STAT1 Transcription Factor; D010768:Phosphoserine; D007372:Interferons; D011505:Protein-Tyrosine Kinases; D053613:Janus Kinase 1; C475466:Kos1 protein, mouse; C098672:TNK1 protein, human
PKC; hepatic immunity; nonreceptor tyrosine kinase; protein kinase C