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The ubiquitin-editing enzyme A20 controls NK cell homeostasis through regulation of mTOR activity and TNF

Jessica Vetters (UGent) , Mary van Helden (UGent) , Sigrid Wahlen, Simon Tavernier (UGent) , Arne Martens (UGent) , Farzaneh Fayazpour (UGent) , Karl Vergote (UGent) , Manon Vanheerswynghels (UGent) , Kim Deswarte (UGent) , Justine Van Moorleghem (UGent) , et al.
(2019) JOURNAL OF EXPERIMENTAL MEDICINE. 216(9). p.2010-2023
Author
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Abstract
The ubiquitin-editing enzyme A20 is a well-known regulator of immune cell function and homeostasis. In addition, A20 protects cells from death in an ill-defined manner. While most studies focus on its role in the TNF-receptor complex, we here identify a novel component in the A20-mediated decision between life and death. Loss of A20 in NK cells led to spontaneous NK cell death and severe NK cell lymphopenia. The few remaining NK cells showed an immature, hyperactivated phenotype, hallmarked by the basal release of cytokines and cytotoxic molecules. NK-A20(-/-) cells were hypersensitive to TNF-induced cell death and could be rescued, at least partially, by a combined deficiency with TNF. Unexpectedly, rapamycin, a well-established inhibitor of mTOR, also strongly protected NK-A20(-/-) cells from death, and further studies revealed that A20 restricts mTOR activation in NK cells. This study therefore maps A20 as a crucial regulator of mTOR signaling and underscores the need for a tightly balanced mTOR pathway in NK cell homeostasis.
Keywords
NATURAL-KILLER-CELLS, HEMATOPOIETIC STEM-CELLS, PROTECTS CELLS, T-CELLS, B-CELL, SURVIVAL, KINASE, MATURATION, BCL-2, OVEREXPRESSION

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MLA
Vetters, Jessica, et al. “The Ubiquitin-Editing Enzyme A20 Controls NK Cell Homeostasis through Regulation of MTOR Activity and TNF.” JOURNAL OF EXPERIMENTAL MEDICINE, vol. 216, no. 9, 2019, pp. 2010–23, doi:10.1084/jem.20182164.
APA
Vetters, J., van Helden, M., Wahlen, S., Tavernier, S., Martens, A., Fayazpour, F., … Janssens, S. (2019). The ubiquitin-editing enzyme A20 controls NK cell homeostasis through regulation of mTOR activity and TNF. JOURNAL OF EXPERIMENTAL MEDICINE, 216(9), 2010–2023. https://doi.org/10.1084/jem.20182164
Chicago author-date
Vetters, Jessica, Mary van Helden, Sigrid Wahlen, Simon Tavernier, Arne Martens, Farzaneh Fayazpour, Karl Vergote, et al. 2019. “The Ubiquitin-Editing Enzyme A20 Controls NK Cell Homeostasis through Regulation of MTOR Activity and TNF.” JOURNAL OF EXPERIMENTAL MEDICINE 216 (9): 2010–23. https://doi.org/10.1084/jem.20182164.
Chicago author-date (all authors)
Vetters, Jessica, Mary van Helden, Sigrid Wahlen, Simon Tavernier, Arne Martens, Farzaneh Fayazpour, Karl Vergote, Manon Vanheerswynghels, Kim Deswarte, Justine Van Moorleghem, Sofie De Prijck, Nozomi Takahashi, Peter Vandenabeele, Louis Boon, Geert van Loo, Eric Vivier, Bart Lambrecht, and Sophie Janssens. 2019. “The Ubiquitin-Editing Enzyme A20 Controls NK Cell Homeostasis through Regulation of MTOR Activity and TNF.” JOURNAL OF EXPERIMENTAL MEDICINE 216 (9): 2010–2023. doi:10.1084/jem.20182164.
Vancouver
1.
Vetters J, van Helden M, Wahlen S, Tavernier S, Martens A, Fayazpour F, et al. The ubiquitin-editing enzyme A20 controls NK cell homeostasis through regulation of mTOR activity and TNF. JOURNAL OF EXPERIMENTAL MEDICINE. 2019;216(9):2010–23.
IEEE
[1]
J. Vetters et al., “The ubiquitin-editing enzyme A20 controls NK cell homeostasis through regulation of mTOR activity and TNF,” JOURNAL OF EXPERIMENTAL MEDICINE, vol. 216, no. 9, pp. 2010–2023, 2019.
@article{8628842,
  abstract     = {{The ubiquitin-editing enzyme A20 is a well-known regulator of immune cell function and homeostasis. In addition, A20 protects cells from death in an ill-defined manner. While most studies focus on its role in the TNF-receptor complex, we here identify a novel component in the A20-mediated decision between life and death. Loss of A20 in NK cells led to spontaneous NK cell death and severe NK cell lymphopenia. The few remaining NK cells showed an immature, hyperactivated phenotype, hallmarked by the basal release of cytokines and cytotoxic molecules. NK-A20(-/-) cells were hypersensitive to TNF-induced cell death and could be rescued, at least partially, by a combined deficiency with TNF. Unexpectedly, rapamycin, a well-established inhibitor of mTOR, also strongly protected NK-A20(-/-) cells from death, and further studies revealed that A20 restricts mTOR activation in NK cells. This study therefore maps A20 as a crucial regulator of mTOR signaling and underscores the need for a tightly balanced mTOR pathway in NK cell homeostasis.}},
  author       = {{Vetters, Jessica and van Helden, Mary and Wahlen, Sigrid and Tavernier, Simon and Martens, Arne and Fayazpour, Farzaneh and Vergote, Karl and Vanheerswynghels, Manon and Deswarte, Kim and Van Moorleghem, Justine and De Prijck, Sofie and Takahashi, Nozomi and Vandenabeele, Peter and Boon, Louis and van Loo, Geert and Vivier, Eric and Lambrecht, Bart and Janssens, Sophie}},
  issn         = {{0022-1007}},
  journal      = {{JOURNAL OF EXPERIMENTAL MEDICINE}},
  keywords     = {{NATURAL-KILLER-CELLS,HEMATOPOIETIC STEM-CELLS,PROTECTS CELLS,T-CELLS,B-CELL,SURVIVAL,KINASE,MATURATION,BCL-2,OVEREXPRESSION}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{2010--2023}},
  title        = {{The ubiquitin-editing enzyme A20 controls NK cell homeostasis through regulation of mTOR activity and TNF}},
  url          = {{http://doi.org/10.1084/jem.20182164}},
  volume       = {{216}},
  year         = {{2019}},
}
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