TY - JOUR
T1 - TBK-binding protein 1 regulates IL-15-induced autophagy and NKT cell survival
AU - Zhu, Lele
AU - Xie, Xiaoping
AU - Zhang, Lingyun
AU - Wang, Hui
AU - Jie, Zuliang
AU - Zhou, Xiaofei
AU - Shi, Jianhong
AU - Zhao, Shuli
AU - Zhang, Boxiang
AU - Cheng, Xuhong
AU - Sun, Shao Cong
N1 - Funding Information:
We thank M. Kronenberg for providing the NKT hybridoma. We also thank the personnel from the NIH/NCI-supported resources (flow cytometry, sequencing, and animal facility) under award number P30CA016672 at The MD Anderson Cancer Center. This work was supported by grants from the National Institutes of Health (AI64639, AI057555, AI104519, and GM84459) and partially supported by a seed fund from the Center for Inflammation and Cancer at the MD Anderson Cancer Center.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - The cytokine IL-15 mediates development and survival of immune cells, including natural killer T (NKT) cells, but the underlying mechanism of IL-15 function is incompletely understood. Here we show that IL-15 induces autophagy in NKT cells with a mechanism that involves a crucial signaling component, TBK-binding protein 1 (Tbkbp1). Tbkbp1 facilitates activation of the autophagy-initiating kinase Ulk1 through antagonizing the inhibitory action of mTORC1. This antagonization involves the recruitment of an mTORC1-opposing phosphatase to Ulk1. Tbkbp1 deficiency attenuates IL-15-stimulated NKT cell autophagy, and is associated with mitochondrial dysfunction, aberrant ROS production, defective Bcl2 expression and reduced NKT cell survival. Consequently, Tbkbp1-deficient mice have profound deficiency in NKT cells, especially IFN-γ-producing NKT1. We further show that Tbkbp1 regulates IL-15-stimulated autophagy and survival of NK cells. These findings suggest a mechanism of autophagy induction by IL-15, and establish Tbkbp1 as a regulator of NKT cell development and survival.
AB - The cytokine IL-15 mediates development and survival of immune cells, including natural killer T (NKT) cells, but the underlying mechanism of IL-15 function is incompletely understood. Here we show that IL-15 induces autophagy in NKT cells with a mechanism that involves a crucial signaling component, TBK-binding protein 1 (Tbkbp1). Tbkbp1 facilitates activation of the autophagy-initiating kinase Ulk1 through antagonizing the inhibitory action of mTORC1. This antagonization involves the recruitment of an mTORC1-opposing phosphatase to Ulk1. Tbkbp1 deficiency attenuates IL-15-stimulated NKT cell autophagy, and is associated with mitochondrial dysfunction, aberrant ROS production, defective Bcl2 expression and reduced NKT cell survival. Consequently, Tbkbp1-deficient mice have profound deficiency in NKT cells, especially IFN-γ-producing NKT1. We further show that Tbkbp1 regulates IL-15-stimulated autophagy and survival of NK cells. These findings suggest a mechanism of autophagy induction by IL-15, and establish Tbkbp1 as a regulator of NKT cell development and survival.
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U2 - 10.1038/s41467-018-05097-5
DO - 10.1038/s41467-018-05097-5
M3 - Article
C2 - 30022064
AN - SCOPUS:85050299858
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2812
ER -