The receptor interaction region of Tyk2 contains a motif required for its nuclear localization.
Janus kinases have so far been viewed as enzymatic intermediates that couple a variety of cell surface receptors to downstream substrates with diverse effector functions. Tyk2 is a member of this family that is involved in the interferon-alpha/beta and interleukin-12 signaling pathways via its specific interaction with the IFNAR1 and the beta1 receptor subunits. Here, we have analyzed the subcellular distribution of the wild-type Tyk2 protein and of several mutants expressed in Tyk2-deficient human cells. Direct GFP-associated fluorescence and immunostaining showed a diffuse localization of Tyk2 throughout the cell, including the nuclear compartment. The nuclear localization of Tyk2 requires a nuclear localization signal-like motif rich in arginine residues that maps within the region mediating interaction with cytokine receptors. To address the question of the role of the Tyk2 nuclear pool in interferon-alpha/beta-induced biological effects, cells expressing a membrane-targeted form of Tyk2-green fluorescent protein were analyzed for their interferon-alpha responses. Our studies demonstrate that Tyk2 can reside in the nucleus independently of receptor binding and that the nuclear pool is dispensable for the transcriptional and anti-vesicular stomatitis virus responses induced by interferon-alpha.
Ragimbeau
J
J
Laboratoire de Signalisation des Cytokines, Institut Pasteur, Paris, France.
Dondi
E
E
Vasserot
A
A
Romero
P
P
Uzé
G
G
Pellegrini
S
S
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D053634:TYK2 Kinase
D016898:Interferon-alpha; D011506:Proteins; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human