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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.

Author information

1
Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX, 77030, USA.
2
Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
3
Department of Pathogenic Biology and Immunology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
4
Central Laboratory, Affiliated Hospital of Hebei University, 212 Yuhua East Road, 07100, Baoding, China.
5
General Clinical Research Center, Nanjing First hospital, Nanjing Medical University, Nanjing, Jiangsu, 210012, China.
6
Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
7
Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX, 77030, USA. ssun@mdanderson.org.
8
The University of Texas Graduate School of Biomedical Sciences, Houston, TX, 77030, USA. ssun@mdanderson.org.

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.

PMID:
30022064
PMCID:
PMC6052109
DOI:
10.1038/s41467-018-05097-5
[Indexed for MEDLINE]
Free PMC Article

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