{"title":"Inhibition of WNK kinases in NK cells disrupts cellular osmoregulation and control of tumor metastasis.","authors":"Ji Sung Kim,John H Kehrl","doi":"10.1159/000540744","DOIUrl":null,"url":null,"abstract":"INTRODUCTION\r\nThe serine/threonine With-No-Lysine (WNK) kinase family function in blood pressure control, electrolyte homeostasis, and cellular osmoregulation. These kinases and their downstream effectors are considered promising therapeutic targets in hypertension and stroke. However, the role of WNK kinases in immune cells remains poorly understood.\r\n\r\nMETHODS\r\nUsing the small-molecule WNK kinase inhibitors WNK463 and WNK-IN-11, we investigated how WNK kinase inhibition affects natural killer (NK) cell physiology.\r\n\r\nRESULTS\r\nWNK kinase inhibition with WNK463 or WNK-IN-11 significantly decreased IL-2-activated NK-cell volume, motility, and cytolytic activity. Treatment of NK cells with these inhibitors induced autophagy by activating AMPK and inhibiting mTOR signaling. Moreover, WNK kinase inhibition increased phosphorylation of Akt and c-Myc by misaligning activity of activating kinases and inhibitory phosphatases. Treatment of tumor-bearing mice with WNK463 impaired tumor metastasis control by adoptively transferred NK cells.\r\n\r\nCONCLUSION\r\nThe catalytic activity of WNK kinases has a critical role of multiple aspects of NK cell physiology and their pharmacologic inhibition negatively impacts NK cell function.","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":"2 1","pages":"1-24"},"PeriodicalIF":4.7000,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Innate Immunity","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1159/000540744","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
INTRODUCTION
The serine/threonine With-No-Lysine (WNK) kinase family function in blood pressure control, electrolyte homeostasis, and cellular osmoregulation. These kinases and their downstream effectors are considered promising therapeutic targets in hypertension and stroke. However, the role of WNK kinases in immune cells remains poorly understood.
METHODS
Using the small-molecule WNK kinase inhibitors WNK463 and WNK-IN-11, we investigated how WNK kinase inhibition affects natural killer (NK) cell physiology.
RESULTS
WNK kinase inhibition with WNK463 or WNK-IN-11 significantly decreased IL-2-activated NK-cell volume, motility, and cytolytic activity. Treatment of NK cells with these inhibitors induced autophagy by activating AMPK and inhibiting mTOR signaling. Moreover, WNK kinase inhibition increased phosphorylation of Akt and c-Myc by misaligning activity of activating kinases and inhibitory phosphatases. Treatment of tumor-bearing mice with WNK463 impaired tumor metastasis control by adoptively transferred NK cells.
CONCLUSION
The catalytic activity of WNK kinases has a critical role of multiple aspects of NK cell physiology and their pharmacologic inhibition negatively impacts NK cell function.
期刊介绍:
The ''Journal of Innate Immunity'' is a bimonthly journal covering all aspects within the area of innate immunity, including evolution of the immune system, molecular biology of cells involved in innate immunity, pattern recognition and signals of ‘danger’, microbial corruption, host response and inflammation, mucosal immunity, complement and coagulation, sepsis and septic shock, molecular genomics, and development of immunotherapies. The journal publishes original research articles, short communications, reviews, commentaries and letters to the editors. In addition to regular papers, some issues feature a special section with a thematic focus.