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PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness
E4BP4, a circadian protein, is indispensable for NK cell development. It remains largely unknown which signal is required to induce E4BP4 expression and what effects it has during NK cell differentiation. Here, we reveal that PDK1, a kinase upstream of mTOR, connects IL-15 signaling to E4BP4. Early...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322053/ https://www.ncbi.nlm.nih.gov/pubmed/25624444 http://dx.doi.org/10.1084/jem.20141703 |
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author | Yang, Meixiang Li, Dan Chang, Zai Yang, Zhongzhou Tian, Zhigang Dong, Zhongjun |
author_facet | Yang, Meixiang Li, Dan Chang, Zai Yang, Zhongzhou Tian, Zhigang Dong, Zhongjun |
author_sort | Yang, Meixiang |
collection | PubMed |
description | E4BP4, a circadian protein, is indispensable for NK cell development. It remains largely unknown which signal is required to induce E4BP4 expression and what effects it has during NK cell differentiation. Here, we reveal that PDK1, a kinase upstream of mTOR, connects IL-15 signaling to E4BP4. Early deletion of PDK1 caused a severe loss of NK cells and compromised antitumor activity in vivo. PDK1-deficient NK cells displayed much weaker IL-15–induced mTOR activation and E4BP4 induction, as well as remarkable reduction in CD122, a receptor subunit specifying NK cell responsiveness to IL-15. The phenotypes were partially reversible by ectopic expression of E4BP4 or bypassed activation of mTOR. We also determined that PDK1-mediated metabolic signaling was dispensable for NK cell terminal maturation and survival. Thus, we identify a role for PDK1 signaling as a key mediator in regulating E4BP4 expression during early NK cell development. Our findings underscore the importance of IL-15 self-responsiveness through a positive feedback loop that involves PDK1–mTOR–E4BP4–CD122 signaling. |
format | Online Article Text |
id | pubmed-4322053 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-43220532015-08-09 PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness Yang, Meixiang Li, Dan Chang, Zai Yang, Zhongzhou Tian, Zhigang Dong, Zhongjun J Exp Med Article E4BP4, a circadian protein, is indispensable for NK cell development. It remains largely unknown which signal is required to induce E4BP4 expression and what effects it has during NK cell differentiation. Here, we reveal that PDK1, a kinase upstream of mTOR, connects IL-15 signaling to E4BP4. Early deletion of PDK1 caused a severe loss of NK cells and compromised antitumor activity in vivo. PDK1-deficient NK cells displayed much weaker IL-15–induced mTOR activation and E4BP4 induction, as well as remarkable reduction in CD122, a receptor subunit specifying NK cell responsiveness to IL-15. The phenotypes were partially reversible by ectopic expression of E4BP4 or bypassed activation of mTOR. We also determined that PDK1-mediated metabolic signaling was dispensable for NK cell terminal maturation and survival. Thus, we identify a role for PDK1 signaling as a key mediator in regulating E4BP4 expression during early NK cell development. Our findings underscore the importance of IL-15 self-responsiveness through a positive feedback loop that involves PDK1–mTOR–E4BP4–CD122 signaling. The Rockefeller University Press 2015-02-09 /pmc/articles/PMC4322053/ /pubmed/25624444 http://dx.doi.org/10.1084/jem.20141703 Text en © 2015 Yang et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Article Yang, Meixiang Li, Dan Chang, Zai Yang, Zhongzhou Tian, Zhigang Dong, Zhongjun PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness |
title | PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness |
title_full | PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness |
title_fullStr | PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness |
title_full_unstemmed | PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness |
title_short | PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness |
title_sort | pdk1 orchestrates early nk cell development through induction of e4bp4 expression and maintenance of il-15 responsiveness |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322053/ https://www.ncbi.nlm.nih.gov/pubmed/25624444 http://dx.doi.org/10.1084/jem.20141703 |
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