ArticleThe Journal of experimental medicine2015
PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness.
Article in The Journal of experimental medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 92 citations in OpenAlex.
- ASB2 inhibits lipid accumulation to promote ILC1 homeostatic fitness and anti-tumor immunity in the mouse liver.Nature communications · 2026Article
- A Microbiota- and IL-15-Dependent Innate-Like B Cell Progenitor Expressing E4BP4.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Clocking immunity: circadian modulation of NK cells and emerging timing perspectives.Frontiers in immunology · 2026Review
- Identification of angiotensin II-responsive circadian clock gene expression in adrenal zona glomerulosa cells and human adrenocortical H295R cells.Frontiers in endocrinology · 2025Article
- GPR34 is a metabolic immune checkpoint for ILC1-mediated antitumor immunity.Nature immunology · 2024Article
- Context-dependent T-BOX transcription factor family: from biology to targeted therapy.Cell communication and signaling : CCS · 2024Review
- Hippo kinases Mst1 and Mst2 maintain NK cell homeostasis by orchestrating metabolic state and transcriptional activity.Cell death & disease · 2024Article
- Dual Activity of Type III PI3K Kinase Vps34 is Critical for NK Cell Development and Senescence.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Article
- Signalling mechanisms driving homeostatic and inflammatory effects of interleukin-15 on tissue lymphocytes.Discovery immunology · 2024Review
- Checkpoint TIPE2 Limits the Helper Functions of NK Cells in Supporting Antitumor CD8Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Twelve-week treadmill endurance training in mice is associated with upregulation of interleukin-15 and natural killer cell activation and increases apoptosis rate in Hepa1-6 cell-derived mouse hepatomas.Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologica · 2023Article
- SUMOylation and related post-translational modifications in natural killer cell anti-cancer responses.Frontiers in cell and developmental biology · 2023Review
- The RNA helicase DHX15 is a critical regulator of natural killer-cell homeostasis and functions.Cellular & molecular immunology · 2022Article
- FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development.Frontiers in immunology · 2022Article
- Natural Killer Cells in Hepatic Ischemia-Reperfusion Injury.Frontiers in immunology · 2022Review
- A cuproptosis-related genes signature associated with prognosis and immune cell infiltration in osteosarcoma.Frontiers in oncology · 2022Article
- A wrinkle in time: circadian biology in pulmonary vascular health and disease.American journal of physiology. Lung cellular and molecular physiology · 2022Article
- TIPE2 is a checkpoint of natural killer cell maturation and antitumor immunity.Science advances · 2021Article
- Declined miR-181a-5p expression is associated with impaired natural killer cell development and function with aging.Aging cell · 2021Article
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.