Interferons induce tyrosine phosphorylation of the eIF2alpha kinase PKR through activation of Jak1 and Tyk2.
The interferon (IFN)-inducible, double-stranded RNA activated protein kinase (PKR) is a dual-specificity kinase, which has an essential role in the regulation of protein synthesis by phosphorylating the translation eukaryotic initiation factor 2 (eIF2). Here, we show the tyrosine (Tyr) phosphorylation of PKR in response to type I or type II IFNs. We show that PKR physically interacts with either Jak1 or Tyk2 in unstimulated cells and that these interactions are increased in IFN-treated cells. We also show that PKR acts as a substrate of activated Jaks, and is phosphorylated at Tyr 101 and Tyr 293 both in vitro and in vivo. Moreover, we provide strong evidence that both the induction of eIF2alpha phosphorylation and inhibition of protein synthesis by IFN are impaired in cells lacking Jak1 or Tyk2, which corresponds to a lack of induction of PKR tyrosine phosphorylation. We conclude that PKR tyrosine phosphorylation provides an important link between IFN signalling and translational control through the regulation of eIF2alpha phosphorylation.
Su
Qiaozhu
Q
Lady Davis Institute, Sir Mortimer B. Davis-Jewish General Hospital, 3999 Cote Ste-Catherine Road, Montreal, Quebec, Canada.
Wang
Shuo
S
Baltzis
Dionissios
D
Qu
Li-Ke
LK
Raven
Jennifer F
JF
Li
Suiyang
S
Wong
Andrew Hoi-Tao
AH
Koromilas
Antonis E
AE
D000818:Animals; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D005786:Gene Expression Regulation / Q000502:physiology*; D015151:Immunoblotting; D007372:Interferons / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology*; D053634:TYK2 Kinase / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism*
D014443:Tyrosine; D007372:Interferons; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse; D019892:eIF-2 Kinase