Proteolytic processing of Stat6 signaling in mast cells as a negative regulatory mechanism

Kotaro Suzuki; Hiroshi Nakajima; Shin-Ichiro Kagami; Akira Suto; Kei Ikeda; Koichi Hirose; Takaki Hiwasa; Kiyoshi Takeda; Yasushi Saito; Shizuo Akira; Itsuo Iwamoto

doi:10.1084/jem.20011682

Proteolytic processing of Stat6 signaling in mast cells as a negative regulatory mechanism

J Exp Med. 2002 Jul 1;196(1):27-38. doi: 10.1084/jem.20011682.

Authors

Kotaro Suzuki¹, Hiroshi Nakajima, Shin-Ichiro Kagami, Akira Suto, Kei Ikeda, Koichi Hirose, Takaki Hiwasa, Kiyoshi Takeda, Yasushi Saito, Shizuo Akira, Itsuo Iwamoto

Affiliation

¹ Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
COS Cells
Cell Division / drug effects
Cell Nucleus / metabolism
Cells, Cultured
DNA-Binding Proteins / metabolism
Feedback, Physiological / physiology*
Genes, Dominant
Interleukin-4 / genetics
Interleukin-4 / metabolism
Interleukin-4 / pharmacology
Mast Cells / cytology
Mast Cells / drug effects
Mast Cells / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Milk Proteins*
Mutagenesis, Site-Directed
Phosphorylation
Protein Isoforms / deficiency
Protein Isoforms / genetics
Protein Isoforms / metabolism
Protein Processing, Post-Translational / physiology*
Receptors, IgE / metabolism
Retroviridae / genetics
STAT5 Transcription Factor
STAT6 Transcription Factor
Serine Endopeptidases / drug effects
Serine Endopeptidases / metabolism
Serine Proteinase Inhibitors / pharmacology
Signal Transduction / physiology*
Trans-Activators / deficiency
Trans-Activators / genetics
Trans-Activators / metabolism*
Transcription, Genetic / physiology
Transfection

Substances

DNA-Binding Proteins
Milk Proteins
Protein Isoforms
Receptors, IgE
STAT5 Transcription Factor
STAT6 Transcription Factor
Serine Proteinase Inhibitors
Stat6 protein, mouse
Trans-Activators
Interleukin-4
Serine Endopeptidases