Proteolytic processing of Stat6 signaling in mast cells as a negative regulatory mechanism.
Accumulating evidence has shown the importance of Stat6-mediated signaling in allergic diseases. In this study, we show a novel regulatory mechanism of Stat6-mediated signaling in mast cells. When Stat6 is activated by interleukin (IL)-4 and translocated to the nucleus, Stat6 is cleaved by a nucleus-associated protease in mast cells. The cleaved 65-kD Stat6 lacks the COOH-terminal transactivation domain and functions as a dominant-negative molecule to Stat6-mediated transcription. The retrovirus-mediated expression of cleavage-resistant Stat6 mutants prolongs the nuclear accumulation of Stat6 upon IL-4 stimulation and enhances IL-4-induced gene expression and growth inhibition in mast cells. These results indicate that the proteolytic processing of Stat6 functions as a lineage-specific negative regulator of Stat6-dependent signaling in mast cells, and thus suggest that it may account for the limited role of Stat6 in IL-4 signaling in mast cells.
Suzuki
Kotaro
K
Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
Nakajima
Hiroshi
H
Kagami
Shin-Ichiro
S
Suto
Akira
A
Ikeda
Kei
K
Hirose
Koichi
K
Hiwasa
Takaki
T
Takeda
Kiyoshi
K
Saito
Yasushi
Y
Akira
Shizuo
S
Iwamoto
Itsuo
I
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019556:COS Cells; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D025461:Feedback, Physiological / Q000502:physiology*; D005799:Genes, Dominant; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017455:Receptors, IgE / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; D012697:Serine Endopeptidases / Q000187:drug effects / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D014162:Transfection
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D020033:Protein Isoforms; D017455:Receptors, IgE; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; D015842:Serine Proteinase Inhibitors; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D012697:Serine Endopeptidases