美国德克萨斯大学西南医学中心Nan Yan研究组最新研究发现，稳定剂TOLLIP可以调节静止状态下STING蛋白的稳定性。相关论文在线发表在2020年1月13日的《自然—免疫学》上。

研究人员发现TOLLIP是STING的稳定剂，其通过直接相互作用防止STING降解。Tollip缺失会导致非造血细胞和组织中STING蛋白质减少，并使STING蛋白质在免疫细胞中不稳定，从而严重削弱了STING信号传导能力。静止态STING的降解需要IRE1α和溶酶体。TOLLIP介导亨廷顿氏病相关polyQ蛋白聚集体的清除。在亨廷顿氏病小鼠纹状体中异位表达的polyQ蛋白或内源性表达的polyQ蛋白会被TOLLIP螯合，从而远离STING，这导致STING蛋白减少，免疫信号减弱。 Tollip ^{– / –}还可改善Trex1 ^{– / –}小鼠中STING介导的自身免疫病。总之，这项发现表明，静止态STING的蛋白水平受到“稳定剂” TOLLIP和“降解剂”IRE1α-溶酶体之间平衡的调节，它们共同维持组织免疫的稳态。

据介绍，STING（干扰素基因刺激物）是一种重要的先天免疫蛋白，但在静止状态下其稳态调节机制尚不清楚。

附：英文原文

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

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

Issue&Volume: 2020-01-13

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.

DOI: 10.1038/s41590-019-0569-9

Source: https://www.nature.com/articles/s41590-019-0569-9