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Homeostatic regulation of STING protein at the resting state by stabilizer TOLLIP

Nature Immunology volume 21, pages 158–167 (2020)Cite this article

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Abstract

STING (stimulator of interferon genes) is an important innate immune protein, but its homeostatic regulation at the resting state is unknown. Here, we identified TOLLIP as a stabilizer of STING through direct interaction to prevent its degradation. Tollip deficiency results in reduced STING protein in nonhematopoietic cells and tissues, and renders STING protein unstable in immune cells, leading to severely dampened STING signaling capacity. The competing degradation mechanism of resting-state STING requires IRE1α and lysosomes. TOLLIP mediates clearance of Huntington’s disease-linked polyQ protein aggregates. Ectopically expressed polyQ proteins in vitro or endogenous polyQ proteins in Huntington’s disease mouse striatum sequester TOLLIP away from STING, leading to reduced STING protein and dampened immune signaling. Tollip–/– also ameliorates STING-mediated autoimmune disease in Trex1–/– mice. Together, our findings reveal that resting-state STING protein level is strictly regulated by a constant tug-of-war between ‘stabilizer’ TOLLIP and ‘degrader’ IRE1α-lysosome that together maintain tissue immune homeostasis.

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Fig. 1: Tollip deficiency impairs STING-mediated IFN signaling.
Fig. 2: TOLLIP prevents lysosomal-mediated degradation of STING at the resting state.
Fig. 3: TOLLIP interacts with STING.
Fig. 4: PolyQ protein disrupts TOLLIP–STING interaction and results in STING protein turnover in vitro and in vivo.
Fig. 5: TOLLIP stabilizes STING protein in cells.
Fig. 6: Tollip deficiency selectively activates IRE1α, which facilitates resting-state STING protein turnover.
Fig. 7: Tollip–/– ameliorates autoinflammatory disease of Trex1–/– mice.
Fig. 8: STING protein level is reduced in Tollip–/– mouse heart tissue.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank M. Maillard (Centre hospitalier universitaire vaudois) for Tollip–/– mice; M. Lehrman (University of Texas Southwestern Medical Center) for Ern1+/+, Ern1–/–, Xbp1+/+ and Xbp1–/– MEFs; U. Deshmukh (Oklahoma Medical Research Foundation) for the initial IHC protocol; and members of the Yan laboratory for helpful discussion. This work was supported by the National Institutes of Health (grant nos. AR067135 and AI134877 to N.Y.; grant nos. NS0870778 and NS052325 to R.G.K.), the Cancer Prevention and Research Institute of Texas (CPRIT, RP180288 to N.Y.) and the Burroughs Wellcome Fund (N.Y.).

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  1. Vladislav Pokatayev

    Present address: The Broad Institute of Harvard and MIT, Cambridge, MA, USA

Authors and Affiliations

  1. Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Vladislav Pokatayev, Kun Yang, Xintao Tu, Nicole Dobbs, Jianjun Wu & Nan Yan

  2. Northwestern University Neurology, Feinberg School of Medicine, Chicago, IL, USA

    Robert G. Kalb

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Contributions

V.P. initiated the project and performed most of the experiments. K.Y. and J.W. helped with some experiments. X.T. and N.D. helped with mouse IHC staining. R.G.K. performed the zQ175 mouse experiment. N.Y. and V.P. wrote the paper with input from all co-authors.

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Correspondence to Nan Yan.

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The authors declare no competing interests.

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Pokatayev, V., Yang, K., Tu, X. et al. Homeostatic regulation of STING protein at the resting state by stabilizer TOLLIP. Nat Immunol 21, 158–167 (2020). https://doi.org/10.1038/s41590-019-0569-9

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