title: PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness.
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.
authors.affiliation: School of Medicine, and Center of Animal Facility, Tsinghua University, Beijing 100086, China.
authors.forename: Meixiang
authors.initials: M
authors.lastname: Yang
authors.affiliation: School of Medicine, and Center of Animal Facility, Tsinghua University, Beijing 100086, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: School of Medicine, and Center of Animal Facility, Tsinghua University, Beijing 100086, China.
authors.forename: Zai
authors.initials: Z
authors.lastname: Chang
authors.affiliation: Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 230032, China.
authors.forename: Zhongzhou
authors.initials: Z
authors.lastname: Yang
authors.affiliation: School of Life Sciences, University of Sciences and Technology of China, Hefei 230026, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
authors.affiliation: School of Medicine, and Center of Animal Facility, Tsinghua University, Beijing 100086, China dongzj@biomed.tsinghua.edu.cn.
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Dong
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D017353:Gene Deletion; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D019409:Interleukin-15 / Q000378:metabolism* / Q000494:pharmacology; D053646:Interleukin-2 Receptor beta Subunit / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D019409:Interleukin-15; D053646:Interleukin-2 Receptor beta Subunit; C497441:Nfil3 protein, mouse; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase