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Proteolytic Processing of Stat6 Signaling in Mast Cells as a Negative Regulatory Mechanism

Kotaro Suzuki¹, Hiroshi Nakajima¹, Shin-ichiro Kagami¹, Akira Suto¹, Kei Ikeda¹, Koichi Hirose¹, Takaki Hiwasa², Kiyoshi Takeda³, Yasushi Saito¹, Shizuo Akira³ and Itsuo Iwamoto¹

¹ Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
² Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
³ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, 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: nakajimh{at}intmed02.m.chiba-u.ac.jp

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.

Key Words: Stat6 • short isoform • proteolysis • mast cells • apoptosis

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