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

Nature Communications
Lele ZhuShao-Cong Sun

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.

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Citations

Feb 2, 2019·Cells·Mojgan Djavaheri-MergnyMagali Humbert
Nov 30, 2018·Frontiers in Immunology·Guan YangLuc Van Kaer
Oct 18, 2020·International Journal of Molecular Sciences·Mirko PesceAntonia Patruno
Jan 1, 2021·International Immunopharmacology·Shuling ZhangFengping Shan

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Methods Mentioned

BETA
lipidation
PMA
flow cytometry
FACS
co-immunoprecipitation
Co-IP
Knockout
Flow
Assay
FCS

Software Mentioned

SlideBook
Prism
ImageJ
GraphPad

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