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

STING 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 resting-state STING protein level 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 (HD)-linked polyQ protein aggregates. Ectopic expression of polyQ protein in vitro or naturally occurring polyQ proteins in HD 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 maintains tissue immune homeostasis.