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Nat Commun. 2018 Jul 18;9(1):2812. doi: 10.1038/s41467-018-05097-5.

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

Zhu L1, Xie X1, Zhang L1,2, Wang H1,3, Jie Z1, Zhou X1, Shi J1,4, Zhao S1,5, Zhang B1,6, Cheng X1, Sun SC7,8.

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Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX, 77030, USA.
Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
Department of Pathogenic Biology and Immunology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
Central Laboratory, Affiliated Hospital of Hebei University, 212 Yuhua East Road, 07100, Baoding, China.
General Clinical Research Center, Nanjing First hospital, Nanjing Medical University, Nanjing, Jiangsu, 210012, China.
Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX, 77030, USA.
The University of Texas Graduate School of Biomedical Sciences, Houston, TX, 77030, USA.


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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