STAT4 requires the N-terminal domain for efficient phosphorylation.
STAT4 (signal transducer and activator of transcription-4) mediates biological effects in response to interleukin-12 (IL-12). STAT4 has multiple domains that have distinct functions in signaling and gene activation. To characterize the role of the STAT4 N-terminal domain in mediating STAT4 biological function, we have generated STAT4-deficient transgenic mice that express human full-length STAT4 or an N-terminal deletion mutant (Delta N-STAT4) lacking the N-terminal 51 amino acids. Whereas full-length STAT4 rescued IL-12 responsiveness, T lymphocytes expressing the STAT4 N-terminal mutant failed to proliferate in response to IL-12 and had limited Th1 cell development as evidenced by minimal interferon-gamma production. Deletion of the N-terminal domain resulted in failure of STAT4 to be phosphorylated following IL-12 stimulation despite similar phosphorylation of JAK2 and TYK2 in full-length STAT4 and Delta N-STAT4 transgenic T cells. We demonstrate that the lack of phosphorylation in cultured cells is due to reduced efficiency of phosphorylation of Delta N-STAT4 by Janus kinases. These data support a new model wherein the N-terminal domain is required to mediate the phosphorylation of STAT4 in addition to the previously documented role in gene transactivation.
Chang
Hua-Chen
HC
Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine, and the Walther Cancer Institute, Indianapolis, Indiana, USA.
Zhang
Shangming
S
Oldham
India
I
Naeger
Lisa
L
Hoey
Timothy
T
Kaplan
Mark H
MH
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D018664:Interleukin-12 / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D050797:STAT4 Transcription Factor; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation
D017931:DNA Primers; D004268:DNA-Binding Proteins; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12