TBK-binding protein 1 regulates IL-15-induced autophagy and NKT cell survival

Lele Zhu, Xiaoping Xie, Lingyun Zhang, Hui Wang, Zuliang Jie, Xiaofei Zhou, Jianhong Shi, Shuli Zhao, Boxiang Zhang, Xuhong Cheng and Shao-Cong Sun ()
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Lele Zhu: The University of Texas MD Anderson Cancer Center
Xiaoping Xie: The University of Texas MD Anderson Cancer Center
Lingyun Zhang: The University of Texas MD Anderson Cancer Center
Hui Wang: The University of Texas MD Anderson Cancer Center
Zuliang Jie: The University of Texas MD Anderson Cancer Center
Xiaofei Zhou: The University of Texas MD Anderson Cancer Center
Jianhong Shi: The University of Texas MD Anderson Cancer Center
Shuli Zhao: The University of Texas MD Anderson Cancer Center
Boxiang Zhang: The University of Texas MD Anderson Cancer Center
Xuhong Cheng: The University of Texas MD Anderson Cancer Center
Shao-Cong Sun: The University of Texas MD Anderson Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-05097-5

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