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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...

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Autores principales: Yang, Meixiang, Li, Dan, Chang, Zai, Yang, Zhongzhou, Tian, Zhigang, Dong, Zhongjun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
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.
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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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