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.
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1 July 2002
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June 24 2002
Proteolytic Processing of Stat6 Signaling in Mast Cells as a Negative Regulatory Mechanism
Kotaro Suzuki,
Kotaro Suzuki
1Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
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Hiroshi Nakajima,
Hiroshi Nakajima
1Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
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Shin-ichiro Kagami,
Shin-ichiro Kagami
1Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
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Akira Suto,
Akira Suto
1Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
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Kei Ikeda,
Kei Ikeda
1Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
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Koichi Hirose,
Koichi Hirose
1Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
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Takaki Hiwasa,
Takaki Hiwasa
2Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
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Kiyoshi Takeda,
Kiyoshi Takeda
3Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
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Yasushi Saito,
Yasushi Saito
1Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
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Shizuo Akira,
Shizuo Akira
3Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
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Itsuo Iwamoto
Itsuo Iwamoto
1Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
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Kotaro Suzuki
1Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
Hiroshi Nakajima
1Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
Shin-ichiro Kagami
1Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
Akira Suto
1Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
Kei Ikeda
1Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
Koichi Hirose
1Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
Takaki Hiwasa
2Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
Kiyoshi Takeda
3Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Yasushi Saito
1Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
Shizuo Akira
3Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Itsuo Iwamoto
1Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
Address correspondence to Hiroshi Nakajima, Department of Internal Medicine II, Chiba University School of Medicine, 1-8-1 Inohana, Chiba City, Chiba 260-8670, Japan. Phone: 81-43-226-2093; Fax: 81-43-226-2095; E-mail: [email protected]
K. Suzuki and H. Nakajima contributed equally to this work.
*
Abbreviations used in this paper: aa, amino acid; AEBSF, 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride; BMMC, bone marrow–derived mast cell; GFP, green fluorescent protein; IRES, internal ribosome entry site; JAK, Janus kinase; MMP, matrix metalloproteinase; MSCV, murine stem cell virus; PCMB, p-chloromercuribenzoate; WT, wild-type.
Received:
October 04 2001
Revision Received:
April 22 2002
Accepted:
May 06 2002
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2002
J Exp Med (2002) 196 (1): 27–38.
Article history
Received:
October 04 2001
Revision Received:
April 22 2002
Accepted:
May 06 2002
Citation
Kotaro Suzuki, Hiroshi Nakajima, Shin-ichiro Kagami, Akira Suto, Kei Ikeda, Koichi Hirose, Takaki Hiwasa, Kiyoshi Takeda, Yasushi Saito, Shizuo Akira, Itsuo Iwamoto; Proteolytic Processing of Stat6 Signaling in Mast Cells as a Negative Regulatory Mechanism . J Exp Med 1 July 2002; 196 (1): 27–38. doi: https://doi.org/10.1084/jem.20011682
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