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

Vladislav Pokatayev, Kun Yang, Xintao Tu, Nicole Dobbs, Jianjun Wu, Robert G. Kalb, Nan Yan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)158-167
Number of pages10
JournalNature Immunology
Volume21
Issue number2
DOIs
StatePublished - Feb 1 2020

Funding

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.).

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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