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Ubiquitylation of an internalized NK cell receptor by Triad3A disrupts sustained NF-κB signaling1
KIR2DL4 (2DL4, CD158d) is a unique killer cell Ig-like receptor (KIR) expressed on human NK cells, which stimulates cytokine production, but mechanisms regulating its expression and function are poorly understood. By yeast two-hybrid screening, we identified the E3 ubiquitin ligase, Triad3A, as an i...
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| Published in: | The Journal of immunology (1950) 2011-01, Vol.186 (5), p.2959-2969 |
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| Main Authors: | , , , , , , |
| Format: | Article |
| Language: | English |
| Online Access: | Get full text |
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| Summary: | KIR2DL4 (2DL4, CD158d) is a unique killer cell Ig-like receptor (KIR) expressed on human NK cells, which stimulates cytokine production, but mechanisms regulating its expression and function are poorly understood. By yeast two-hybrid screening, we identified the E3 ubiquitin ligase, Triad3A, as an interaction partner for the 2DL4 cytoplasmic domain. The protein interaction was confirmed
in vivo
, and Triad3A expression induced polyubiquitylation and degradation of 2DL4. Overexpression of Triad3A selectively abrogated cytokine-producing function of 2DL4, while Triad3A shRNA reversed ubiquitylation and restored cytokine production. Expression of Triad3A in an NK cell line did not affect receptor surface expression, internalization, or early signaling, but significantly reduced receptor turnover and suppressed sustained NF-κB activation. 2DL4 endocytosis was found to be vital to stimulate cytokine production, and Triad3A expression diminished localization of internalized receptor in early endosomes. Our results reveal a critical role for endocytosed 2DL4 receptor to generate sustained NF-κB signaling and drive cytokine production. We conclude that Triad3A is a key negative regulator of sustained 2DL4-mediated NF-κB signaling from internalized 2DL4, which functions by promoting ubiquitylation and degradation of endocytosed receptor from early endosomes. “This is an author-produced version of a manuscript accepted for publication in
The Journal of Immunology
(
The JI
). The American Association of Immunologists, Inc. (AAI), publisher of
The JI
, holds the copyright to this manuscript. This version of the manuscript has not yet been copyedited or subjected to editorial proofreading by
The JI
; hence, it may differ from the final version published in
The JI
(online and in print). AAI (
The JI
) is not liable for errors or omissions in this author-produced version of the manuscript or in any version derived from it by the U.S. National Institutes of Health or any other third party. The final, citable version of record can be found at
www.jimmunol.org
.” |
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| ISSN: | 0022-1767 1550-6606 |
| DOI: | 10.4049/jimmunol.1000112 |